Novel carbocyclic compounds as ror gamma modulators

ABSTRACT

The present disclosure is directed to novel carbocyclic compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , n, m and p are as defined herein, which are active as modulators of retinoid-related orphan receptor gamma t (RORγt). These compounds prevent, inhibit, or suppress the action of RORγt and are therefore useful in the treatment of RORγt mediated diseases, disorders, syndromes or conditions such as, e.g., pain, inflammation, COPD, asthma, rheumatoid arthritis, colitis, multiple sclerosis, psoriasis, neurodegenerative diseases and cancer.

RELATED APPLICATIONS

This application claims the benefit of Indian Provisional ApplicationNo. 3299/MUM/2015 filed on Aug. 28, 2015; which is hereby incorporatedby reference in its entirety.

TECHNICAL FIELD

The present patent application is directed to novel carbocycliccompounds which may be useful as retinoid-related orphan receptor gammat (RORγt) modulators.

BACKGROUND OF THE INVENTION

Retinoid-related orphan receptors (RORs) are transcription factors whichbelong to the steroid hormone nuclear receptor super family. The RORfamily consists of three members, ROR alpha (RORα), ROR beta (RORβ) andROR gamma (RORγ), also known as NR1F1, NR1F2 and NR1F3 respectively (andeach encoded by a separate gene RORA, RORB and RORC, respectively). RORscontain four principal domains shared by the majority of nuclearreceptors: an N-terminal A/B domain, a DNA-binding domain, a hingedomain, and a ligand binding domain. Each ROR gene generates severalisoforms which differ only in their N-terminal A/B domain. Two isoformsof RORγ, RORγ1 and RORγt (also known as RORγ2) have been identified.

RORγt is a truncated form of RORγ, lacking the first N-terminal 21 aminoacids and is exclusively expressed in cells of the lymphoid lineage andembryonic lymphoid tissue inducers (Sun et al., Science, 2000, 288,2369-2372; Eberl et al., Nat Immunol., 2004, 5: 64-73) in contrast toRORγ which is expressed in multiple tissues (heart, brain, kidney, lung,liver and muscle).

RORγt has been identified as a key regulator of Th17 celldifferentiation. Th17 cells are a subset of T helper cells which produceIL-17 and other proinflammatory cytokines and have been shown to havekey functions in several mouse autoimmune disease models includingexperimental autoimmune encephalomyelitis (EAE) and collagen-inducedarthritis (CIA). In addition, Th17 cells have also been associated inthe pathology of a variety of human inflammatory and autoimmunedisorders including multiple sclerosis, rheumatoid arthritis, psoriasis,Crohn's disease and asthma (Jetten et al., Nucl. Recept. Signal, 2009,7:e003; Manel et al., Nat. Immunol., 2008, 9, 641-649). The pathogenesisof chronic autoimmune diseases including multiple sclerosis andrheumatoid arthritis arises from the break in tolerance towardsself-antigens and the development of auto-aggressive effector T cellsinfiltrating the target tissues. Studies have shown that Th17 cells areone of the important drivers of the inflammatory process intissue-specific autoimmunity (Steinman et al., J. Exp. Med., 2008, 205:1517-1522; Leung et al., Cell. Mol. Immunol., 2010 7: 182-189). Th17cells are activated during the disease process and are responsible forrecruiting other inflammatory cell types, especially neutrophils, tomediate pathology in the target tissues (Korn et al., Annu. Rev.Immunol., 2009, 27:485-517) and RORγt has been shown to play a criticalrole in the pathogenic responses of Th17 cells (Ivanov et al., Cell,2006 126: 1121-1133). RORγt deficient mice have shown no Th17 cells andalso resulted in amelioration of EAE. The genetic disruption of RORγ ina mouse colitis model also prevented colitis development (Buonocore etal., Nature, 2010, 464: 1371-1375). The role of RORγt in thepathogenesis of autoimmune or inflammatory diseases has been welldocumented in the literature. (Jetten et al., Adv. Dev. Biol., 2006,16:313-355; Meier et al. Immunity, 2007, 26:643-654; Aloisi et al., Nat.Rev. Immunol., 2006, 6:205-217; Jager et al., J. Immunol., 2009,183:7169-7177; Serafmi et al., Brain Pathol., 2004, 14: 164-174;Magliozzi et al., Brain, 2007, 130: 1089-1104; Barnes et al., Nat. Rev.Immunol., 2008, 8: 183-192).

In addition, RORγt is also shown to play a crucial role in othernon-Th17 cells, such as mast cells (Hueber et al., J Immunol., 2010,184: 3336-3340). RORγt expression and secretion of Th17-type ofcytokines has also been reported in NK T-cells (Eberl et al., Nat.Immunol., 2004, 5: 64-73) and gamma-delta T-cells (Sutton et al, Nat.Immunol., 2009, 31: 331-341; Louten et al., J Allergy Clin. Immunol.,2009, 123: 1004-1011), suggesting an important function for RORγt inthese cells.

PCT Publication Nos. WO 2012/139775, WO 2012/027965, WO 2012/028100, WO2012/100732, WO 2012/100734, WO2012/064744, WO 2013/171729 and WO2015/008234 disclose heterocyclic compounds which are modulators ofretinoid-related orphan receptor gamma (RORγ) receptor activity.

In view of the above, a need exists for new therapeutic agents thatmodulate the activity of RORγt and thus will provide new methods fortreating diseases or conditions associated with the modulation of RORγt.

The present application is directed to compounds that are modulators ofthe RORγt receptor.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a compound of formula(I)

or a tautomer thereof, stereoisomer thereof or pharmaceuticallyacceptable salt thereof, wherein

R¹ is selected from amino, hydroxyl, C₁₋₈alkyl and C₁₋₈alkoxy;

R² is selected from C₁₋₈alkyl, haloC₁₋₈alkyl, hydroxyC₁₋₈alkyl,C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₈alkyl;

R³ is selected from hydrogen, C₁₋₈alkyl, haloC₁₋₈alkyl andhydroxyC₁₋₈alkyl;

R⁴ is selected from C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl,hydroxyC₁₋₈alkyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₈alkyl;

each occurrence of R⁵ is independently selected from halogen, hydroxyl,cyano, C₁₋₈ alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl, haloC₁₋₈alkoxy,hydroxyC₁₋₈alkyl, C₃₋₆cycloalkyl and optionally substituted C₆₋₁₄aryl,wherein the substitution on C₆₋₁₄aryl is halogen;

each occurrence of R⁶ is independently selected from halogen, cyano,hydroxyl, C₁₋₈ alkyl and C₃₋₆cycloalkyl;

R^(a) and R^(b), which may be same or different, are each independentlyselected from hydrogen and C₁₋₈alkyl; or R^(a) and R^(b) together mayform an oxo group;

‘n’ is 1, 2, 3 or 4;

‘m’ is 0, 1 or 2; and

‘p’ is 0 or 1.

The compounds of formula (I) may involve one or more embodiments.Embodiments of compounds of formula (I) include compounds of formula(II) as described hereinafter. It is to be understood that theembodiments below are illustrative of the present invention and are notintended to limit the claims to the specific embodiments exemplified. Itis also to be understood that the embodiments defined herein may be usedindependently or in conjunction with any definition and any otherembodiment defined herein. Thus the invention contemplates all possiblecombinations and permutations of the various independently describedembodiments. For example, the invention provides compounds of formula(I) as defined above wherein R² is methyl or 2,2,2-trifluoroethyl(according to an embodiment defined below); R³ is hydrogen (according toanother embodiment defined below); and ‘m’ is 0 (according to yetanother embodiment defined below).

According to one embodiment, specifically provided are compounds offormula (I), in which R¹ is amino (—NH₂), hydroxyl (—OH), C₁₋₈alkyl(e.g. methyl) or C₁₋₈alkoxy (e.g. methoxy or ethoxy).

According to another embodiment, specifically provided are compounds offormula (I), in which R¹ is amino, hydroxyl, methyl, methoxy or ethoxy.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R² is C₁₋₈alkyl (e.g. methyl) or haloC₁₋₈alkyl(e.g. 2,2,2-trifluoroethyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R² is methyl or 2,2,2-trifluoroethyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R³ is hydrogen.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R⁴ is C₁₋₈alkyl (e.g. methyl) or C₃₋₆cycloalkyl(e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R⁴ is methyl or cyclopropyl.

According to yet another embodiment specifically provided are compoundsof formula (I), in which R³ is hydrogen; R⁴ is methyl or cyclopropyl and‘p’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R⁵ is halogen (e.g. fluoroor chloro), C₁₋₈alkyl (e.g. methyl), C₃₋₆cycloalkyl (e.g. cyclopropyl)or optionally substituted C₆₋₁₄aryl (e.g. 2-fluorophenyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each occurrence of R⁵ is fluoro, chloro,methyl, cyclopropyl or 2-fluorophenyl.

According to yet another embodiment specifically provided are compoundsof formula (I), in which R^(a) and R^(b) are hydrogen.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which one of R^(a) and R^(b) is hydrogen and theother is C₁₋₈alkyl (e.g. methyl).

According to yet another embodiment specifically provided are compoundsof formula (I), in which one of R^(a) and R^(b) is hydrogen and theother is methyl.

According to yet another embodiment specifically provided are compoundsof formula (I), in which R^(a) and R^(b) are C₁₋₈alkyl (e.g. methyl).

According to yet another embodiment specifically provided are compoundsof formula (I), in which R^(a) and R^(b) are methyl.

According to yet another embodiment specifically provided are compoundsof formula (I), in which R^(a) and R^(b) together forms oxo group.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘m’ is 0.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘n’ is 1, 2 or 3.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘p’ is 0.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘p’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which

is 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl, 2-chloro-4-cyclopropylphenyl,2-chloro-5-cyclopropylphenyl, 3-chloro-2-fluorophenyl,3-chloro-5-fluorophenyl, 2-chloro-4-methylphenyl,2-chloro-5-methylphenyl, 2-chloro-6-methylphenyl,4-chloro-2-methylphenyl, 2-cyclopropyl-4-methylphenyl,5-cyclopropyl-2-methylphenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-fluoro-5-methylphenyl,2-chloro-4,6-dimethylphenyl, 4-chloro-2-fluoro-5-methylphenyl ormesityl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which

R¹ is amino, hydroxyl, methyl, methoxy or ethoxy;

R² is methyl or 2,2,2-trifluoroethyl;

R³ is hydrogen; R⁴ is methyl or cyclopropyl;

R⁵ is fluoro, chloro, methyl, cyclopropyl or 2-fluorophenyl;

R^(a) is hydrogen or methyl;

R^(b) is hydrogen or methyl; or R^(a) and R^(b) together forms oxogroup;

‘m’ is 0;

‘n’ is 1, 2 or 3; and

‘p’ is 0 or 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which

R¹ is amino, hydroxyl, methyl, methoxy or ethoxy;

R² is methyl or 2,2,2-trifluoroethyl;

R³ is hydrogen; R⁴ is methyl or cyclopropyl;

is 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl, 2-chloro-4-cyclopropylphenyl,2-chloro-5-cyclopropylphenyl, 3-chloro-2-fluorophenyl,3-chloro-5-fluorophenyl, 2-chloro-4-methylphenyl,2-chloro-5-methylphenyl, 2-chloro-6-methylphenyl,4-chloro-2-methylphenyl, 2-cyclopropyl-4-methylphenyl,5-cyclopropyl-2-methylphenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-fluoro-5-methylphenyl,2-chloro-4,6-dimethylphenyl, 4-chloro-2-fluoro-5-methylphenyl ormesityl;

‘m’ is 0;

‘n’ is 1, 2 or 3; and

‘p’ is 0 or 1.

According to yet another embodiment, the definition of “compounds offormula (I)” inherently includes all stereoisomers of the compound offormula (I) either as pure stereoisomer or as a mixture of two or morestereomers. The word stereoisomers includes enantiomers,diasteroisomers, racemates, cis isomers, trans isomers and mixturethereof.

According to yet another embodiment, the compounds of formula (I) is acompound that may exist in the form of one or more stereoisomers,wherein one or more of those steroisomers is therapeutically active.

According to yet another embodiment, the compounds of formula (I)comprises a therapeutically active stereoisomer that is substantiallyfree of other stereoisomers.

According to yet another embodiment, compounds of formula (I) comprisesa therapeutically active stereoisomer that has less than about 50%, lessthan about 40%, less than about 30%, less than about 20%, less thanabout 10%, less than about 5%, or less than about 1% by weight of othersteroisomers.

According to an embodiment, specifically provided are compounds offormula (I) with an IC₅₀ value of less than 500 nM, preferably less than100 nM, more preferably less than 50 nM, with respect to RORγt activity.

Further embodiments relating to groups R¹, R², R⁴, R⁵, R^(a), R^(b), m,n, p (and groups defined therein) are described hereinafter in relationto the compounds of formula (II) and formula (III). It is to beunderstood that these embodiments are not limited to use in conjunctionwith formula (II) or formula (III), but apply independently andindividually to the compounds of formula (I). For example, in anembodiment described hereinafter, the invention specifically providescompounds of formula (II) or formula (III), wherein R² is methyl or2,2,2-trifluoroethyl and consequently there is also provided a compoundof formula (I) in which R² is methyl or 2,2,2-trifluoroethyl.

The invention also provides a compound of formula (II), which is anembodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (II)

or a tautomer thereof, stereoisomer thereof or pharmaceuticallyacceptable salt thereof, wherein

R¹ is selected from amino, hydroxyl, C₁₋₈alkyl and C₁₋₈alkoxy;

R² is selected from C₁₋₈alkyl, haloC₁₋₈alkyl, hydroxyC₁₋₈alkyl,C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₈alkyl;

each occurrence of R⁵ is independently selected from halogen, hydroxyl,cyano, C₁₋₈ alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl, haloC₁₋₈alkoxy,hydroxyC₁₋₈alkyl, C₃₋₆cycloalkyl and optionally substituted C₆₋₁₄aryl,wherein the substitution on C₆₋₁₄aryl is halogen;

R^(a) and R^(b), which may be same or different, are each independentlyselected from hydrogen and C₁₋₈alkyl; or R^(a) and R^(b) together mayform an oxo group; and

‘n’ is 1, 2, 3 or 4;

The compounds of formula (II) may involve one or more embodiments. It isto be understood that the embodiments below are illustrative of thepresent invention and are not intended to limit the claims to thespecific embodiments exemplified. It is also to be understood that theembodiments defined herein may be used independently or in conjunctionwith any definition, any other embodiment defined herein. Thus theinvention contemplates all possible combinations and permutations of thevarious independently described embodiments. For example, the inventionprovides compounds of formula (II) as defined above wherein, R^(a) andR^(b) are hydrogen (according to an embodiment defined below), R¹ isamino, hydroxyl, methyl, methoxy or ethoxy (according to anotherembodiment defined below) and R² is methyl or 2,2,2-trifluoroethyl(according to yet another embodiment defined below).

According to one embodiment, specifically provided are compounds offormula (II), in which R¹ is amino (—NH₂), hydroxyl (—OH), C₁₋₈alkyl(e.g. methyl) or C₁₋₈alkoxy (e.g. methoxy or ethoxy).

According to another embodiment, specifically provided are compounds offormula (II), in which R¹ is amino, hydroxyl, methyl, methoxy or ethoxy.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which R² is C₁₋₈alkyl (e.g. methyl) or haloC₁₋₈alkyl(e.g. 2,2,2-trifluoroethyl).

According to yet another embodiment, specifically provided are compoundsof formula (II), in which R² is methyl or 2,2,2-trifluoroethyl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R⁵ is halogen (e.g. fluoroor chloro), C₁₋₈alkyl (e.g. methyl), C₃₋₆cycloalkyl (e.g. cyclopropyl)or optionally substituted C₆₋₁₄aryl (e.g. 2-fluorophenyl).

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each occurrence of R⁵ is fluoro, chloro,methyl, cyclopropyl or 2-fluorophenyl.

According to yet another embodiment specifically provided are compoundsof formula (II), in which R^(a) and R^(b) are hydrogen.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which one of R^(a) and R^(b) is hydrogen and theother is C₁₋₈alkyl (e.g. methyl).

According to yet another embodiment specifically provided are compoundsof formula (II), in which one of R^(a) and R^(b) is hydrogen and theother is methyl.

According to yet another embodiment specifically provided are compoundsof formula (II), in which R^(a) and R^(b) are C₁₋₈alkyl (e.g. methyl).

According to yet another embodiment specifically provided are compoundsof formula (II), in which R^(a) and R^(b) are methyl.

According to yet another embodiment specifically provided are compoundsof formula (II), in which R^(a) and R^(b) together forms oxo group.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which ‘n’ is 1, 2 or 3.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which

is 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl, 2-chloro-4-cyclopropylphenyl,2-chloro-5-cyclopropylphenyl, 3-chloro-2-fluorophenyl,3-chloro-5-fluorophenyl, 2-chloro-4-methylphenyl,2-chloro-5-methylphenyl, 2-chloro-6-methylphenyl,4-chloro-2-methylphenyl, 2-cyclopropyl-4-methylphenyl,5-cyclopropyl-2-methylphenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-fluoro-5-methylphenyl,2-chloro-4,6-dimethylphenyl, 4-chloro-2-fluoro-5-methylphenyl ormesityl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which

R¹ is amino, hydroxyl, methyl, methoxy or ethoxy;

R² is methyl or 2,2,2-trifluoroethyl;

R⁵ is fluoro, chloro, methyl, cyclopropyl or 2-fluorophenyl;

R^(a) is hydrogen or methyl;

R^(b) is hydrogen or methyl; or R^(a) and R^(b) together forms oxogroup; and

‘n’ is 1, 2 or 3.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which

R¹ is amino, hydroxyl, methyl, methoxy or ethoxy;

R² is methyl or 2,2,2-trifluoroethyl;

R^(a) is hydrogen or methyl;

R^(b) is hydrogen or methyl; or R^(a) and R^(b) together forms oxogroup; and

is 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl, 2-chloro-4-cyclopropylphenyl,2-chloro-5-cyclopropylphenyl, 3-chloro-2-fluorophenyl,3-chloro-5-fluorophenyl, 2-chloro-4-methylphenyl,2-chloro-5-methylphenyl, 2-chloro-6-methylphenyl,4-chloro-2-methylphenyl, 2-cyclopropyl-4-methylphenyl,5-cyclopropyl-2-methylphenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-fluoro-5-methylphenyl,2-chloro-4,6-dimethylphenyl, 4-chloro-2-fluoro-5-methylphenyl ormesityl.

According to an embodiment, specifically provided are compounds offormula (II) with an IC₅₀ value of less than 500 nM, preferably lessthan 100 nM, more preferably less than 50 nM, with respect to RORγtactivity.

The invention also provides a compound of formula (III), which is anembodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (III)

or a tautomer thereof, stereoisomer thereof or pharmaceuticallyacceptable salt thereof, wherein

R¹ is selected from amino, hydroxyl, C₁₋₈alkyl and C₁₋₈alkoxy;

R² is selected from C₁₋₈alkyl, haloC₁₋₈alkyl, hydroxyC₁₋₈alkyl,C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₈alkyl;

R⁴ is selected from C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl,hydroxyC₁₋₈alkyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₈alkyl;

each occurrence of R⁵ is independently selected from halogen, hydroxyl,cyano, C₁₋₈ alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl, haloC₁₋₈alkoxy,hydroxyC₁₋₈alkyl, C₃₋₆cycloalkyl and optionally substituted C₆₋₁₄aryl,wherein the substitution on C₆₋₁₄aryl is halogen;

R^(a) and R^(b), which may be same or different, are each independentlyselected from hydrogen and C₁₋₈alkyl; or R^(a) and R^(b) together mayform an oxo group; and

‘n’ is 1, 2, 3 or 4;

The compounds of formula (III) may involve one or more embodiments. Itis to be understood that the embodiments below are illustrative of thepresent invention and are not intended to limit the claims to thespecific embodiments exemplified. It is also to be understood that theembodiments defined herein may be used independently or in conjunctionwith any definition, any other embodiment defined herein. Thus theinvention contemplates all possible combinations and permutations of thevarious independently described embodiments. For example, the inventionprovides compounds of formula (III) as defined above wherein R¹ ishydroxyl, methyl or methoxy (according to an embodiment defined below),R⁴ is methyl or cyclopropyl (according to another embodiment definedbelow) and ‘n’ is 1 (according to yet another embodiment defined below).

According to one embodiment, specifically provided are compounds offormula (III), in which R¹ is hydroxyl (—OH), C₁₋₈alkyl (e.g. methyl) orC₁₋₈alkoxy (e.g. methoxy).

According to another embodiment, specifically provided are compounds offormula (III), in which R¹ is hydroxyl, methyl or methoxy.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which R² is C₁₋₈alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compoundsof formula (III), in which R² is methyl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which R⁴ is C₁₋₈alkyl (e.g. methyl) orC₃₋₆cycloalkyl (e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compoundsof formula (III), in which R⁴ is methyl or cyclopropyl.

According to yet another embodiment specifically provided are compoundsof formula (III), in which each occurrence of R⁵ is halogen (e.g.chloro).

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R⁵ is chloro.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each occurrence of R⁵ is chloro and ‘n’ is 1.

According to yet another embodiment specifically provided are compoundsof formula (III), in which R^(a) and R^(b) are hydrogen.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which one of R^(a) and R^(b) is hydrogen and theother is C₁₋₈alkyl (e.g. methyl).

According to yet another embodiment specifically provided are compoundsof formula (III), in which one of R^(a) and R^(b) is hydrogen and theother is methyl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which ‘n’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which

is 4-chlorophenyl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which

R¹ is hydroxyl, methyl or methoxy;

R² is methyl;

R⁴ is methyl or cyclopropyl;

R⁵ is chloro;

R^(a) is hydrogen;

R^(b) is hydrogen or methyl; and

‘n’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which

R¹ is hydroxyl, methyl or methoxy;

R² is methyl;

R⁴ is methyl or cyclopropyl;

R^(a) is hydrogen;

R^(b) is hydrogen or methyl; and

is 4-chlorophenyl.

According to an embodiment, specifically provided are compounds offormula (III) with an IC₅₀ value of less than 500 nM, preferably lessthan 100 nM, more preferably less than 50 nM, with respect to RORγtactivity.

Compounds of the present invention include the compounds in Examples1-40. It should be understood that the formulas (I), (II) and (III)structurally encompasses all geometrical isomers, stereoisomers,enantiomers and diastereomers, N-oxides, and pharmaceutically acceptablesalts that may be contemplated from the chemical structure of the generadescribed herein.

The present application also provides a pharmaceutical composition thatincludes at least one compound described herein and at least onepharmaceutically acceptable excipient (such as a pharmaceuticallyacceptable carrier or diluent). Preferably, the pharmaceuticalcomposition comprises a therapeutically effective amount of at least onecompound described herein. The compounds described herein may beassociated with a pharmaceutically acceptable excipient (such as acarrier or a diluent) or be diluted by a carrier, or enclosed within acarrier which can be in the form of a tablet, capsule, sachet, paper orother container.

The compounds and pharmaceutical compositions of the present inventionare useful for inhibiting the activity of RORγt. Thus, the presentinvention further provides a method of inhibiting RORγt in a subject inneed thereof by administering to the subject one or more compoundsdescribed herein in an amount effective to cause inhibition of suchreceptor.

In a further aspect, the present invention relates to a method oftreating a disease, disorder or condition modulated by RORγt, such as anautoimmune disease, inflammatory disease, respiratory disorder, pain andcancer comprising administering to a subject in need thereof a compoundaccording to any of the embodiments described herein.

In another aspect, the present invention relates to a method of treatinga disease, disorder or condition modulated by RORγt, such as chronicobstructive pulmonary disease (COPD), asthma, cough, pain, inflammatorypain, chronic pain, acute pain, arthritis, osteoarthritis, multiplesclerosis, rheumatoid arthritis, colitis, ulcerative colitis andinflammatory bowel disease, comprising administering to a subject inneed thereof a compound according to any of the embodiments describedherein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms “halogen” or “halo” means fluorine (fluoro), chlorine(chloro), bromine (bromo), or iodine (iodo).

The term “alkyl” refers to a hydrocarbon chain radical that includessolely carbon and hydrogen atoms in the backbone, containing nounsaturation, having from one to eight carbon atoms (i.e. C₁₋₈alkyl),and which is attached to the rest of the molecule by a single bond, suchas, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). Theterm “C₁₋₈alkyl” refers to an alkyl chain having 1 to 8 carbon atoms.The term “C₁₋₄alkyl” refers to an alkyl chain having 1 to 4 carbonatoms.

Unless set forth or recited to the contrary, all alkyl groups describedor claimed herein may be straight chain or branched.

The term “alkoxy” denotes an alkyl group attached via an oxygen linkageto the rest of the molecule (e.g. C₁₋₈ alkoxy). Representative examplesof such groups are —OCH₃ and —OC₂H₅. Unless set forth or recited to thecontrary, all alkoxy groups described or claimed herein may be straightchain or branched.

The term “haloalkyl” refers to at least one halo group (selected from F,Cl, Br or I), linked to an alkyl group as defined above (i.e.haloC₁₋₈alkyl). Examples of such haloalkyl groups include, but are notlimited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Theterm “haloC₁₋₈alkyl” refers to at least one halo group linked an alkylchain having 1 to 8 carbon atoms. Unless set forth or recited to thecontrary, all haloalkyl groups described herein may be straight chain orbranched.

The term “haloalkoxy” refers to an alkoxy group substituted with one ormore halogen atoms (i.e. haloC₁₋₈alkoxy). Examples of “haloalkoxy”include but are not limited to fluoromethoxy, difluoromethoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy,pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and1-bromoethoxy. Unless set forth or recited to the contrary, allhaloalkoxy groups described herein may be straight chain or branched.

The term “hydroxyC₁₋₈alkyl” refers to an C₁₋₈alkyl group as definedabove wherein one to three hydrogen atoms on different carbon atoms arereplaced by hydroxyl groups (i.e. hydroxyC₁₋₄alkyl). Examples ofhydroxyC₁₋₈alkyl moieties include, but are not limited to —CH₂OH and—C₂H₄OH.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of 3 to about 12 carbon atoms, (i.e. C₃₋₁₂cycloalkyl). Examplesof monocyclic cycloalkyl include but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicycliccycloalkyl groups include, but are not limited to, perhydronapthyl,adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclicgroups, e.g., spiro(4,4)non-2-yl. The term “C₃₋₆cycloalkyl” refers tothe cyclic ring having 3 to 6 carbon atoms. Examples of “C₃₋₆cycloalkyl”include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radicalhaving 3 to about 6 carbon atoms directly attached to an alkyl group(e.g. C₃₋₆cycloalkylC₁₋₈alkyl). The cycloalkylalkyl group may beattached to the main structure at any carbon atom in the alkyl groupthat results in the creation of a stable structure. Non-limitingexamples of such groups include cyclopropylmethyl, cyclobutylethyl, andcyclopentylethyl.

The term “aryl” refers to an aromatic radical having 6 to 14 carbonatoms (i.e. C₆₋₁₄aryl), including monocyclic, bicyclic and tricyclicaromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl,and biphenyl.

The term “pharmaceutically acceptable salt” includes salts prepared frompharmaceutically acceptable bases or acids including inorganic ororganic bases and inorganic or organic acids. Examples of such saltsinclude, but are not limited to, acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate,carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, phosphate, diphosphate, polygalacturonate,salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide and valerate. Examples of salts derivedfrom inorganic bases include, but are not limited to, aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,manganic, mangamous, potassium, sodium, and zinc.

The term “treating” or “treatment” of a state, disorder or conditionincludes: (a) preventing or delaying the appearance of clinical symptomsof the state, disorder or condition developing in a subject that may beafflicted with or predisposed to the state, disorder or condition butdoes not yet experience or display clinical or subclinical symptoms ofthe state, disorder or condition; (b) inhibiting the state, disorder orcondition, i.e., arresting or reducing the development of the disease orat least one clinical or subclinical symptom thereof; or (c) relievingthe disease, i.e., causing regression of the state, disorder orcondition or at least one of its clinical or subclinical symptoms.

The term “subject” includes mammals (especially humans) and otheranimals, such as domestic animals (e.g., household pets including catsand dogs) and non-domestic animals (such as wildlife).

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a subject for treating a state, disorder orcondition, is sufficient to effect such treatment. The “therapeuticallyeffective amount” will vary depending on the compound, the disease andits severity and the age, weight, physical condition and responsivenessof the subject to be treated.

The compounds of formula (I), (II) or (III) may contain asymmetric orchiral centers, and, therefore, exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of formula(I), (II) or (III) as well as mixtures thereof, including racemicmixtures, form part of the present invention. In addition, the presentinvention embraces all geometric and positional isomers. Diastereomericmixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods well known tothose skilled in the art, such as, for example, by chromatography and/orfractional crystallization. Enantiomers can be separated by convertingthe enantiomeric mixture into a diastereomeric mixture by the reactionwith an appropriate optically active compound (e.g., chiral auxiliarysuch as a chiral alcohol or Mosher's acid chloride), separating thediastereomers and converting (e.g., hydrolysing) the individualdiastereomers to the corresponding pure enantiomers. Enantiomers canalso be separated by use of chiral HPLC column. The chiral centers ofthe present invention can have the S or R configuration as defined bythe IUPAC 1974.

Pharmaceutical Compositions

The compounds of the invention are typically administered in the form ofa pharmaceutical composition. The pharmaceutical compositions describedherein comprise one or more compounds described herein and one or morepharmaceutically acceptable excipients. Typically, the pharmaceuticallyacceptable excipients are approved by regulatory authorities or aregenerally regarded as safe for human or animal use. The pharmaceuticallyacceptable excipients include, but are not limited to, carriers,diluents, glidants and lubricants, preservatives, buffering agents,chelating agents, polymers, gelling agents, viscosifyingu agents,solvents and the like.

Examples of suitable carriers include, but are not limited to, water,salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil,gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate,sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia,stearic acid, lower alkyl ethers of cellulose, silicic acid, fattyacids, fatty acid amines, fatty acid monoglycerides and diglycerides,fatty acid esters, and polyoxyethylene.

The pharmaceutical compositions described herein may also include one ormore pharmaceutically acceptable auxiliary agents, wetting agents,suspending agents, preserving agents, buffers, sweetening agents,flavouring agents, colorants or any combination of the foregoing.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using anyroute of administration, such as orally or parenterally. The route ofadministration may be any route which effectively transports the activecompound of the patent application to the appropriate or desired site ofaction.

Methods of Treatment

The compounds of the present invention are particularly useful becausethey inhibit the activity of retinoid-related orphan receptor gamma,particularly retinoid-related orphan receptor gamma t (RORγt), i.e.,they prevent, inhibit, or suppress the action of RORγt, and/or mayelicit a RORγt modulating effect. Compounds of the invention aretherefore useful in the treatment of those conditions in whichinhibition of ROR gamma activity, and particularly RORγt, is beneficial.

The compounds of the present patent application are modulators of RORγtand can be useful in the treatment of diseases or disorder mediated byRORγt. Accordingly, the compounds and the pharmaceutical compositions ofthis invention may be useful in the treatment of inflammatory, metabolicand autoimmune diseases mediated by RORγt.

The term “autoimmune diseases” will be understood by those skilled inthe art to refer to a condition that occurs when the immune systemmistakenly attacks and destroys healthy body tissue. An autoimmunedisorder may result in the destruction of one or more types of bodytissue, abnormal growth of an organ, and changes in organ function. Anautoimmune disorder may affect one or more organ or tissue types whichinclude, but are not limited to, blood vessels, connective tissues,endocrine glands such as the thyroid or pancreas, joints, muscles, redblood cells, and skin. Examples of autoimmune (or autoimmune-related)disorders include multiple sclerosis, arthritis, rheumatoid arthritis,psoriasis, Crohn's disease, gastrointestinal disorder, inflammatorybowel disease, irritable bowel syndrome, colitis, ulcerative colitis,Sjorgen's syndrome, atopic dermatitis, optic neuritis, respiratorydisorder, chronic obstructive pulmonary disease (COPD), asthma, type Idiabetes, neuromyelitis optica, Myasthenia Gavis, uveitis,Guillain-Barre syndrome, psoriatic arthritis, Gaves' disease, allergy,osteoarthritis, Kawasaki disease, mucosal leishmaniasis, Hashimoto'sthyroiditis, Pernicious anemia, Addison's disease, Systemic lupuserythematosus, Dermatomyositis, Sjogren syndrome, Lupus erythematosus,Myasthenia gravis, Reactive arthritis, Celiac disease—sprue(gluten-sensitive enteropathy), Graves's disease, thymopoiesis andLupus.

Compounds of the present patent application may also be useful in thetreatment of inflammation. The term “inflammation” will be understood bythose skilled in the art to include any condition characterized by alocalized or a systemic protective response, which may be elicited byphysical trauma, infection, chronic diseases, and/or chemical and/orphysiological reactions to external stimuli (e.g. as part of an allergicresponse). Any such response, which may serve to destroy, dilute orsequester both the injurious agent and the injured tissue, may bemanifest by, for example, heat, swelling, pain, redness, dilation ofblood vessels and/or increased blood flow, invasion of the affected areaby white.

The term “inflammation” is also understood to include any inflammatorydisease, disorder or condition per se, any condition that has aninflammatory component associated with it, and/or any conditioncharacterized by inflammation as a symptom, including inter alia acute,chronic, ulcerative, specific, allergic, infection by pathogens, immunereactions due to hypersensitivity, entering foreign bodies, physicalinjury, and necrotic inflammation, and other forms of inflammation knownto those skilled in the art. The term thus also includes, for thepurposes of this present patent application, inflammatory pain, paingenerally and/or fever.

The compounds of the present invention may be used for treatment ofarthritis, including, but are not limited to, rheumatoid arthritis,osteoarthritis, psoriatic arthritis, septic arthritis,spondyloarthropathies, gouty arthritis, systemic lupus erythematosus andjuvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) andother arthritic conditions.

The compounds of the present invention may be used for treatment ofrespiratory disorders including, but are not limited to, chronicobstructive pulmonary disease (COPD), asthma, bronchospasm, and cough.

Other respiratory disorders include, but are not limited to, bronchitis,bronchiolitis, bronchiectasis, acute nasoparyngitis, acute and chronicsinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngitis,tracheitis, epiglottitis, croup, chronic disease of tonsils andadenoids, hypertrophy of tonsils and adenoids, peritonsillar abscess,rhinitis, abscess or ulcer and nose, pneumonia, viral and bacterialpneumonia, bronchopneumonia, influenza, extrinsic allergic alveolitis,coal workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy,respiratory conditions due to chemical fumes, vapors and other externalagents, emphysema, pleurisy, pneumothorax, abscess of lung andmediastinum, pulmonary congestion and hypostasis, postinflammatorypulmonary fibrosis, other alveolar and parietoalveolar pneumonopathy,idiopathic fibrosing alveolitis, Hamman-Rich syndrome, atelectasis,ARDS, acute respiratory failure, and mediastinitis.

The compounds of the present invention may also be used for treatment ofpain conditions. The pain can be acute or chronic pain. Thus, thecompounds of the present invention may be used for treatment of e.g.,inflammatory pain, arthritic pain, neuropathic pain, post-operativepain, surgical pain, visceral pain, dental pain, premenstrual pain,central pain, cancer pain, pain due to burns, migraine or clusterheadaches, nerve injury, neuritis, neuralgias, poisoning, ischemicinjury, interstitial cystitis, viral, parasitic or bacterial infection,post-traumatic injury, or pain associated with irritable bowel syndrome.

The compounds of the present invention may further be used for treatmentof gastrointestinal disorder such as, but not limited to, irritablebowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis,biliary colic and other biliary disorders, renal colic,diarrhea-dominant IBS, and pain associated with gastrointestinaldistension.

In addition, the compounds of the present invention may be useful in thetreatment of cancer, and pain associated with cancer. Such cancersinclude, e.g., multiple myeloma and bone disease associated withmultiple myeloma, melanoma, medulloblastoma, acute myelogenous leukemia(AML), head and neck squamous cell carcinoma, hepatocellular carcinoma,gastric cancer, bladder carcinoma and colon cancer.

The compounds of the present invention may be useful in a treatment ofdisease, disorder, syndrome or condition selected from the groupconsisting of chronic obstructive pulmonary disease (COPD), asthma,cough, pain, inflammatory pain, chronic pain, acute pain, arthritis,osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis,ulcerative colitis and inflammatory bowel disease.

Any of the methods of treatment described herein comprise administeringan effective amount of a compound according to Formula (I), (II) or(III), or a pharmaceutically-acceptable salt thereof, to a subject(particularly a human) in need thereof.

The present inventions further relates to the use of the compoundsdescribed herein in the preparation of a medicament for the treatment ofdiseases mediated by RORγt.

The compounds of the invention are effective both in the therapeuticand/or prophylactic treatment of the above-mentioned conditions. For theabove-mentioned therapeutic uses the dosage administered may vary withthe compound employed, the mode of administration, the treatment desiredand the disorder.

The daily dosage of the compound of the invention administered may be inthe range from about 0.05 mg/kg to about 100 mg/kg.

General Methods of Preparation

The compounds, described herein, including those of general formula(Ia), (Ib), (Ic), (Ib-i), (IIa), various intermediates and specificexamples are prepared through the synthetic methods as depicted inSchemes 1 to 10. Furthermore, in the following schemes, where specificacids, bases, reagents, coupling reagents, solvents, etc. are mentioned,it is understood that other suitable acids, bases, reagents, couplingreagents, solvents etc. may be used and are included within the scope ofthe present invention. The modifications to reaction conditions, forexample, temperature, duration of the reaction or combinations thereof,are envisioned as part of the present invention. The compounds obtainedusing the general reaction sequences may be of insufficient purity.These compounds can be purified using any of the methods forpurification of organic compounds known to persons skilled in the art,for example, crystallization or silica gel or alumina columnchromatography using different solvents in suitable ratios. All possiblegeometrical isomers and stereoisomers are envisioned within the scope ofthis invention.

The starting materials used herein are commercially available or wereprepared by methods known in the art to those of ordinary skill or bymethods disclosed herein. In general, the intermediates and compounds ofthe present invention can be prepared through the reaction schemes asfollows. In some cases the final product may be further modified, forexample, by manipulation of substituents. These manipulations mayinclude, but are not limited to, reduction, oxidation, alkylation,acylation, hydrolysis, and cleavage of protecting groups etc., byfollowing procedures known in the art of organic synthesis.

A general approach for the preparation of compounds of the formulae(Ia), (Ib) and (Ic) (wherein R¹, R², R³, R⁴, R⁵, R⁶, ‘n’, ‘m’ and ‘p’are as defined with respect to a compound of formula (I) & R^(a) andR^(b) are C₁₋₈ alkyl in formulae (Ib) and (Ic)) is depicted in syntheticscheme 1.

The acid-amine coupling of compound of formula (1) with compound offormula (2) in the presence of a suitable coupling agent(s) and suitablebase gives compound of formula (Ia). The suitable coupling agent(s) maybe 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),N,N′-dicyclohexylcarbodiimide (DCC), propyl phosphonic anhydride (T3P)or (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU). The suitable base used in thereaction may be Et₃N, DIPEA, pyridine or DMAP. The acid amine couplingreaction may be carried out in a suitable solvent such as CH₂Cl₂, CHCl₃,DMF and THF or mixture thereof. Alternatively, coupling of compound offormula (1) with compound of formula (3) in the presence of a suitablecoupling agent(s) and suitable base gives the keto compound of formula(4). The reduction of keto group of compound of formula (4) usingsuitable reducing agent in a suitable solvent gives the correspondingracemic hydroxyl compound of formula (Ib). The suitable reducing agentmay be sodium borohydride and the suitable solvent may be methanol.Alternatively, compound of formula (4) on reaction with suitableGrignard reagent of formula (22) (wherein R^(a) is C₁₋₈ alkyl and X ishalogen) in a suitable solvent such as THF gives compound of formula(Ic).

An alternate approach for the preparation of compounds of the formulae(Ib) (wherein R², R³, R⁴, R⁵, R⁶, ‘n’, ‘m’ and ‘p’ are as defined withrespect to a compound of formula (I) & R^(b) is C₁₋₈ alkyl) is depictedin synthetic scheme 2.

The acid-amine coupling of compound of formula (1) with compound offormula (5) in the presence of a suitable coupling agent(s) and suitablebase gives ester compound of formula (6). The suitable coupling agent(s)may be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),N,N′-dicyclohexylcarbodiimide (DCC), propyl phosphonic anhydride (T3P)or (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU). The suitable base used in thereaction may be Et₃N, DIPEA, pyridine or DMAP. The acid amine couplingreaction may be carried out in a suitable solvent such as CH₂Cl₂, CHCl₃,DMF and THF or mixture thereof. The reaction of alkyl lithium compoundof formula R^(b)—Li with the ester compound of formula (6) in thepresence of suitable solvent gives the ketone compound of formula (4).The reduction of keto group of compound of formula (4) using suitablereducing agent in a suitable solvent gives the corresponding racemichydroxyl compound of formula (Ib). The suitable reducing agent may besodium borohydride and the suitable solvent may be methanol.

A general approach for the preparation of compounds of the formulae(Ib-i) (wherein R¹, R², R³, R⁴, R⁵, R⁶, ‘n’, ‘m’ and ‘p’ are as definedwith respect to a compound of formula (I) & R^(b) is C₁₋₈ alkyl) isdepicted in synthetic scheme 3.

The chiral reduction of keto group of compound of formula (4) usingsuitable chiral reducing agent in a suitable solvent yields one of theisomer of hydroxyl compound of formula (Ib-i) as a major product. Thechiral reduction may be carried out using (R orS)-2-methyl-CBS-oxazaborolidine in the presence of borane dimethylsulfide, hydrogenation using BINAP-Ru dihalide, H₂/ruthenium(diphosphane)₂ (diamine)₂ complex, etc. The suitable solvent may be THF,DCM or DMF. The obtained isomer may be further purified according tovarious purification techniques known in the art.

An approach for the preparation of compound of formula (IIa) (whereinR², R⁵, and ‘n’, are as defined with respect to a compound of formula(I)) is depicted in the synthetic scheme 4.

The acid-amine coupling of amine compound of formula (Ia) withcarboxylic acid of formula (5) in the presence of a suitable couplingagent(s) and suitable base gives ester compound of formula (6a). Thesuitable coupling agent(s) may be1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),N,N′-dicyclohexylcarbodiimide (DCC), propyl phosphonic anhydride (T3P)or (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU). The suitable base used in thereaction may be Et₃N, DIPEA, pyridine or DMAP. The reduction of theester group of compound of formula (6a) using suitable reducing agentsuch as sodium borohydride in a suitable polar solvent such as methanolgives the hydroxyl compound of formula (IIa).

A general approach for the preparation of compound of formula (2)(wherein R, is as defined with respect to a compound of formula (I)) isdepicted in the synthetic scheme 5.

The reaction of halo substituted phenyl keto compound of formula (7)(wherein Hal is halogen) with ethane 1,2-dithiol in the presence of asuitable Lewis acid in a suitable solvent gives the thioacetal compoundof formula (8). The suitable Lewis acid may be boron trifluoridediethyletherate and suitable solvent may be selected from CH₂Cl₂, CHCl₃,DMF and THF. The compound of formula (8) on reaction with HF-pyridinecomplex in the presence of N-iodosuccinimide gives benzyldifluoro-compound of formula (9). Substitution reaction on compound offormula (9) with tert-butyl acetate in the presence of palladiumcatalyst and suitable base gives compound of formula (10). The suitablebase may be lithium dicyclohexylamine. The compound of formula (10) ondeprotection of tert-butyl group, using trifluoroacetic acid in asuitable solvent furnishes the carboxylic acid of formula (2). Thesuitable solvent may be selected from CH₂Cl₂, CHCl₃, DMF and THF.

A general approach for the preparation of compound of formula (3)(wherein R^(b) is C₁₋₈ alkyl) is depicted in the synthetic scheme 6.

The condensation of suitably substituted halo phenyl acetic acidcompound of formula (11) (wherein Hal is halogen) with ethylbromo(difluoro)acetate gives the difluoro ester compound of formula(12). The acid group in compound of formula (12) is protected withtert-butyl bromide to give compound of formula (13). Selectivehydrolysis of ethyl ester in compound of formula (13) using lithiumhydroxide monohydrate in a suitable solvent gives the acid compound offormula (14). The suitable solvent may be THF, methanol, water ormixture thereof. The reaction of compound (14) with oxalyl chloridegives the corresponding acid chloride which on reaction withN,O-dimethylhydroxylamine hydrochloride in the presence of a base and ina suitable solvent gives the Weinreb amide compound of formula (15). Thesuitable solvent used may be CH₂Cl₂ or THF. The compound of formula (15)on reaction with alkyl lithium or suitable Grignard reagent in asuitable solvent such as THF gives the ketone compound of formula (16).The ester hydrolysis of compound of formula (16) using suitable reagentsuch as trifluoroacetic acid in a suitable solvent such as CH₂Cl₂affords the carboxylic acid compound of formula (3).

An approach for the preparation of compound of formula (23) (wherein R′is C₁₋₈ alkyl) is depicted in the synthetic scheme 7.

The reaction of di-halo compound of formula (17) (wherein Hal₁ and Hal₂are halogen) with ethyl bromo(difluoro)acetate in the presence of copperpowder and suitable solvent gives the difluoro ester compound of formula(18). The compound of formula (18) on reduction using suitable reducingagent in suitable conditions gives the hydroxyl compound of formula(19). The suitable reducing agent may be sodium borohydride and thesolvent can be selected from methanol, IPA or ethanol. The reaction ofcompound of formula (19) with an alkylating compound of formula (20)(where R′ is C₁₋₈alkyl and X is halogen) using a suitable base in asuitable solvent gives the compound of formula (21). The suitable basemay be sodium hydride and the solvent may be selected from CH₂Cl₂,CHCl₃, DMF and THF or combination thereof. The halo-substitution ofcompound of formula (21) with tert-butyl acetate in the presence ofpalladium catalyst gives compound of formula (22). The compound offormula (22) on treatment with trifluoroacetic acid in a suitablesolvent such as THF affords the carboxylic acid compound of formula(23).

A general approach for the preparation of compound of formula (Ia)(wherein R², R⁵ and ‘n’, are as defined with respect to a compound offormula (I)) is depicted in the synthetic scheme 8.

The reaction of suitably substituted amine of formula (24) with an acylhalide compound of formula (25) (wherein X is halogen) in the presenceof a suitable base under suitable reaction conditions gives the amidecompound of formula (26). The suitable base may be Et₃N, DIPEA, pyridineor DMAP. The reaction may be carried out in a suitable solvent, selectedfrom CH₂Cl₂, CHCl₃, DMF and THF or combination thereof. The reaction ofcompound of formula (26) with an alkylating agent of formula (27) (whereX is halogen) using a suitable base such as sodium hydride givescompound of formula (28). The reduction of nitro group of compound offormula (28) using iron powder in the presence of aqueous acetic acid orammonium chloride yields the corresponding amine compound of formula(Ia).

A general approach for the synthesis of compound of formula (Ib)(wherein R², R⁴, R⁵ and ‘n’, are as defined with respect to a compoundof formula (I)) is depicted in synthetic scheme 9.

A suitably substituted alkyl aryl ketone of formula (29) on reactionwith (R)-2-methylpropane-2-sulfinamide in the presence of a suitabledehydrating agent gives the imine compound of formula (30). Thereduction of imino group of compound of formula (30) using sodiumborohydride in a suitable solvent gives predominantly the(R),(R)-diastereomer compound of formula (31). The suitable solvent maybe THF. The acid catalyzed reaction of compound of formula (31) forremoval of chiral auxiliary gives the amine compound of formula (32) asits acid addition salt. The coupling of amine compound of formula (32)with acid chloride compound of formula (25) in the presence of suitablebase provides the amide compound of formula (33). The alkylation ofcompound of formula (33) using a suitable alkyl halide of formula (27)in the presence of suitable base such as sodium hydride gives thecompound of formula (34). The reduction of compound of formula (34) ironpowder in the presence of aqueous acetic acid or ammonium chlorideaffords the amine compound of formula (Ib).

A general approach for the preparation of compounds of formulae (Ic)(wherein R⁵ and ‘n’, are as defined with respect to a compound offormula (I)) is depicted in the synthetic scheme 10.

The reaction of suitably substituted amine compound of formula (24) withtrifluoroacetic anhydride in the presence of suitable base gives theamide compound of formula (35). The suitable base may be triethylamineor N,N′-diisopropylethylamine. The amide compound of formula (35) onreduction using borane dimethylsulfide yields the corresponding aminecompound of formula (36) which on coupling with acyl halide compound offormula (25) (wherein X is halogen) in the presence of a suitable baseunder suitable reaction conditions gives the nitro compound of formula(37). The suitable base may be Et₃N, DIPEA, pyridine or DMAP. Thereaction may be carried out in a suitable solvent or mixture thereof.The suitable solvent may be selected from CH₂Cl₂, CHCl₃, DMF and THF orcombination thereof. The reduction of nitro group of compound of formula(37) using iron powder in the presence of aqueous acetic acid orammonium chloride yields the corresponding amine compound of formula(Ic).

EXPERIMENTAL SECTION

Unless otherwise stated, work-up includes distribution of the reactionmixture between the organic and aqueous phase indicated withinparentheses, separation of layers and drying the organic layer oversodium sulfate, filtration and evaporation of the solvent. Purification,unless otherwise mentioned, includes purification by silica gelchromatographic techniques, generally using ethyl acetate/petroleumether mixture of a suitable polarity as the mobile phase. Use of adifferent eluent system is indicated within parentheses.

The abbreviations, symbols and terms used in the examples and assayshave the following meanings throughout: DCM: dichloromethane; DMSO-d₆:Hexadeuterodimethyl sulfoxide; DMSO dimethyl sulfoxide; ¹H NMR: ProtonNuclear Magnetic Resonance; DMF: N,N-dimethyl formamide; EDCI.HCl:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBT:1-hydroxybenzotriazole; NaOH: Sodium Hydroxide; KOH: PotassiumHydroxide; LiOH: Lithium Hydroxide; DIPEA: N,N-diisopropylethylamine;THF: Tetrahydofuran; HCl: hydrochloric acid; Na₂SO₄: Sodium sulfate; J:Coupling constant in units of Hz; h: hour(s); RT or rt: Room temperature(22-26° C.); o: ortho; m:meta; p: para; APCI-MS: Atmospheric PressureChemical Ionization Mass Spectrometry; MHz: Megahertz

Intermediates Intermediate 14-Amino-N-(4-chlorophenyl)-N-methylbenzamide

Step 1: N-(4-Chlorophenyl)-4-nitrobenzamide

To a stirred solution of 4-chloroaniline (2.5 g, 19.59 mmol) andtriethylamine (8.2 mL, 58.79 mmol) in dichloromethane (20 mL) at 0° C.was added 4-nitrobenzoyl chloride (3.64 g, 19.59 mmol). The mixture wasstirred for 3 h at RT. The reaction mixture was poured into water (50mL) and extracted with ethyl acetate (150 mL×3). The combined organiclayers were washed with brine (200 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The crude material obtained wastriturated in diethyl ether to yield 4.2 g of the titled product. ¹H NMR(300 MHz, DMSO-d₆) δ 7.44 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H),8.17 (d, J=8.7 Hz, 2H), 8.39 (d, J=8.7 Hz, 2H), 10.68 (s, 1H).

Step 2: N-(4-Chlorophenyl)-N-methyl-4-nitrobenzamide

To a stirred solution of Step 1 intermediate (4.08 g, 14.74 mmol) in DMF(20 mL) was added sodium hydride (60% w/w, 766 mg, 19.16 mmol) at 0° C.and the mixture was stirred for 10□15 min at RT. Methyl iodide (1.1 mL,17.69 mmol) was added to the mixture and stirred at RT for 3 h. Thereaction was quenched with aqueous ammonium chloride (30 mL) and pouredinto water (40 mL). The aqueous mixture was extracted with ethyl acetate(150 mL×2). The combined organic layers were washed with brine (200 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue obtained was triturated in diethyl etherto yield 4.1 g of the desired compound. The intermediate was as suchtaken for the next step without characterization.

Step 3: 4-Amino-N-(4-chlorophenyl)-N-methylbenzamide

To a suspension of Step 2 intermediate (4.2 g, 14.45 mmol) and ammoniumchloride (7.7 g, 145 mmol) in a mixture of ethanol and water (5:1, 120mL) at 90° C. was added iron powder (2.42 g, 43.35 mmol) and the mixturewas stirred at 90° C. for 1 h. The reaction mixture was cooled to RT andethanol was distilled out under vacuum to obtain a thick residue. Theresidue was diluted with ethyl acetate (100 mL), washed with aqueoussodium bicarbonate (100 mL) and brine (100 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated to yield3.2 g of the titled product. ¹H NMR (300 MHz, DMSO-d₆) δ 3.29 (s, 3H),5.48 (s, 2H), 6.32 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 7.12 (d,J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H); ESI-MS (m/z) 261 (M+H)⁺.

Intermediate 2 2-(4-(2-Ethoxy-1,1-difluoro-2-oxoethyl)phenyl)acetic acid

To a stirred suspension of 4-iodophenylacetic acid (203 mg, 0.76 mmol)and copper powder (193 mg, 3.05 mmol) in DMSO (8.0 mL) was added ethylbromodifluoroacetate (196 mg, 1.52 mmol) at RT. The reaction mixture wasstirred overnight at 60° C. in a sealed tube. The mixture was cooled toRT and quenched with aqueous ammonium chloride (30 mL). The aqueousmixture was further diluted with water (20 mL) and extracted with ethylacetate (50 mL×2). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatographyto yield 171 mg of the titled product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.22(t, J=7.2 Hz, 3H), 3.67 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 7.44 (d, J=8.1Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 12.44 (s, 1H).

Intermediate 3 2-(4-(1,1-Difluoropropyl)phenyl)acetic acid

Step 1: 2-(4-Bromophenyl)-2-ethyl-1,3-dithiolane

To a stirred solution of 4-bromopropiophenone (2.01 g, 9.43 mmol) inanhydrous dichloromethane (20 mL) were added boron trifluoridediethyletherate (0.49 mL, 4.71 mmol) and ethane 1,2-dithiol (1.57 mL,18.8 mmol). The reaction mixture was stirred overnight at RT. Themixture was diluted with dichloromethane (10 mL), washed with 10%aqueous sodium hydroxide solution (10 mL), water (20 mL) followed bybrine (20 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to yield 2.21g of the titled compound. ¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, J=7.5 Hz,3H), 2.33 (q, J=7.5 Hz, 2H), 3.18-3.30 (m, 2H), 3.33-3.41 (m, 2H), 7.41(d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H); APCI-MS (m/z) 288 (M)⁺.

Step 2: 1-Bromo-4-(1,1-difluoropropyl)benzene

To a stirred solution of N-iodosuccinimide (704 mg, 3.13 mmol) indichloromethane (5.0 mL) at −20° C. were added hydrogen fluoride inpyridine (70%, 0.52 mL, 20.88 mmol). After being stirred for 2 min, asolution of Step 1 intermediate (302 mg, 1.04 mmol) in dichloromethane(5.0 mL) was added and resulting mixture was stirred at −20° C. for 30min. The reaction mixture was diluted with n-hexane (5.0 mL), filteredthrough basic alumina and the bed was washed with n-hexane (30 mL). Thecombined filtrates were concentrated and the residue obtained wasdiluted with ethyl acetate (50 mL). The solution was washed with 10%sodium thiosulfate (20 mL), 2% potassium permanganate (20 mL), water (20mL) and brine (20 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The residue obtained was purified bysilica gel column chromatography to yield 203 mg of the titled product.¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.5 Hz, 3H), 2.02-2.21 (m, 2H),7.33 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H).

Step 3: tert-Butyl 2-(4-(1,1-difluoropropyl)phenyl)acetate

To a solution of dicyclohexylamine (1.8 g, 10.25 mmol) in anhydroustoluene (20 mL) at 0° C. was added n-butyl lithium (6.41 mL, 10.26 mmol,1.6 M in hexane). After 5 min, tert-butyl acetate (1.15 mL, 8.55 mmol)was added to the mixture and stirred for 15 min at 0° C. In a separateflask, tri-tert-butylphosphonium tetrafluoroborate (248 mg, 0.85 mmol)and bis(dibenzylideneacetone) palladium (0) (245 mg, 0.42 mmol) weretaken together and was evacuated and refilled with nitrogen thrice. Thesolid mixture was suspended in toluene (10 mL) and to this was addedStep 2 intermediate (2.01 g, 8.55 mmol) followed by the first reactionmixture. The resulting mixture was stirred overnight at RT. The reactionmixture was diluted with diethyl ether (50 mL), filtered through celitebed and the bed was washed with diethyl ether (30 mL). The combinedfiltrates were concentrated and the residue obtained was purified bysilica gel column chromatography to yield 1.43 g of the titled product.1H NMR (300 MHz, CDCl₃) δ 0.98 (t, J=7.5 Hz, 3H), 1.44 (s, 9H),2.04-2.22 (m, 2H), 3.55 (s, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1Hz, 2H).

Step 4: 2-(4-(1,1-Difluoropropyl)phenyl)acetic acid

To a stirred solution of Step 3 intermediate (1.42 g, 5.25 mmol) indichloromethane (20 mL) at 0° C. was added trifluoroacetic acid (10 mL)and the mixture was stirred at RT for 1 h. The solvent was evaporatedand the residue obtained was purified by silica gel columnchromatography to afford 491 mg of the titled product. ¹H NMR (300 MHz,DMSO-d₆) δ 0.90 (t, J=6.0 Hz, 3H), 2.11-2.28 (m, 2H), 3.63 (s, 2H), 7.33(d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 12.42 (br s, 1H); APCI-MS(m/z) 213 (M−H)⁻.

Intermediate 4 2-(4-(1,1-Difluoro-2-oxopropyl)phenyl)acetic acid

Step 1: Ethyl2-(4-(2-(tert-butoxy)-2-oxoethyl)phenyl)-2,2-difluoroacetate

To a stirred solution of2-(4-(2-ethoxy-1,1-difluoro-2-oxoethyl)phenyl)acetic acid (Intermediate2) (3.3 g, 12.77 mmol) in a mixture of dichloromethane and THF (2:1, 90mL) were added molecular sieves (3.3 g, 4 Å) and silver carbonate (10.58g, 38.33 mmol). The reaction mixture was stirred, cooled to 0° C. andwas added tert-butyl bromide (7.3 mL, 63.89 mmol) dropwise. The mixturewas stirred overnight at RT. The reaction mixture was filtered throughcelite bed and washed with dichloromethane (100 mL). The filtrate wasconcentrated under reduced pressure and the residue obtained waspurified by flash chromatography to yield 1.82 g of the titled product.The product was used for next step without characterisation.

Step 2: 2-(4-(2-(tert-Butoxy)-2-oxoethyl)phenyl)-2,2-difluoroacetic acid

To a stirred solution of Step 1 intermediate (915 mg, 2.91 mmol) in amixture of THF, methanol and water (3:2:1, 30 mL) at 0° C. was addedlithium hydroxide monohydrate (366 mg, 8.73 mmol) and the mixture wasstirred for 1 h at RT. The reaction mixture was acidified with 1 N HCltill pH 2-3 and extracted with ethyl acetate (50 mL×2). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford 839 mg of the titledproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 1.40 (s, 9H), 3.64 (s, 2H), 7.40(d, J=8.4 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H).

Step 3: tert-Butyl2-(4-(1,1-difluoro-2-(methoxy(methyl)amino)-2-oxoethyl) phenyl)acetate

To a stirred solution of Step 2 intermediate (833 mg, 2.90 mmol) indichloromethane (15 mL) at 0° C. were added oxalyl chloride (2.2 mL,4.36 mmol) and 2 drops of DMF. The mixture was warmed to RT and stirredfor 3 h. The mixture was concentrated under inert atmosphere to give anoily residue, which was diluted with dichloromethane (15 mL). Thesolution was cooled to 0° C. and was added N, O-dimethyl hydroxylaminehydrochloride (425 mg, 4.36 mmol) followed by triethylamine (1.6 mL,11.63 mmol). The mixture was stirred overnight at RT. The mixture wasdiluted with dichloromethane (15 mL), washed with aqueous saturatedsodium bicarbonate solution (20 mL) and brine (20 mL). The organic layerwas dried over anhydrous sodium sulfate, filtered, concentrated and theresidue obtained was purified by silica gel column chromatography toyield 581 mg of the desired product. ¹H NMR (300 MHz, CDCl₃) δ 1.43 (s,9H), 3.21 (s, 3H), 3.51 (s, 2H), 3.56 (s, 3H), 7.34 (d, J=7.8 Hz, 2H),7.50 (d, J=7.8 Hz, 2H).

Step 4: tert-Butyl 2-(4-(1,1-difluoro-2-oxopropyl)phenyl)acetate

To a stirred solution of Step 3 intermediate (572 mg, 1.73 mmol) in THF(15 mL) at 0° C. was added methylmagnesium bromide (1.15 mL, 3.47 mmol)and the mixture was stirred at 0° C. for 2 h. The reaction was quenchedwith aqueous ammonium chloride solution (20 mL) and extracted with ethylacetate (50 mL×2). The combined organic layers were washed with brine(50 mL), concentrated and the crude obtained was purified by silica gelcolumn chromatography to yield 369 mg of the desired product. ¹H NMR(300 MHz, CDCl₃) δ 1.43 (s, 9H), 2.31 (s, 3H), 3.56 (s, 2H), 7.36 (d,J=8.4 Hz, 2H), 7.50 (d, J=7.8 Hz, 2H), APCI-MS (m/z) 286 (M+H)⁺.

Step 5: 2-(4-(1,1-Difluoro-2-oxopropyl)phenyl)acetic acid

The titled compound was prepared by the reaction of Step 4 intermediate(501 mg, 1.76 mmol) with trifluoroacetic acid (10 mL) in dichloromethane(10 mL) as per the procedure described in Step 4 of Intermediate 3 toafford 379 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.36 (s, 3H),3.66 (s, 2H), 7.43 (d, J=7.8 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 12.22 (brs, 1H).

Intermediate 5 4-Amino-N-(2,5-dichlorophenyl)-N-methylbenzamide

Step 1: N-(2,5-Dichlorophenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of 2,5-dichloroaniline(223 mg, 1.37 mmol) and 4-nitrobenzoyl chloride (256 mg, 1.37 mmol) inpyridine (5.0 mL) at refluxed temperature as per the procedure describedin Step 1 of Intermediate 1 to yield 314 mg of the product. ¹H NMR (300MHz, DMSO-d₆) δ 7.41 (d, J=8.7 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.76 (s,1H), 8.19 (d, J=8.1 Hz, 2H), 8.39 (d, J=8.4 Hz, 2H), 10.55 (s, 1H).

Step 2: N-(2,5-Dichlorophenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(309 mg, 0.99 mmol) with methyl iodide (93 μL, 1.48 mmol) using sodiumhydride (60% w/w, 51.63 mg, 1.29 mmol) in anhydrous DMF (5.0 mL) as perthe procedure described in step 2 of Intermediate 1 to yield 294 mg ofthe product. ¹H NMR (300 MHz, CDCl₃) δ 3.40 (s, 3H), 7.19 (d, J=5.7 Hz,2H), 7.25-7.32 (m, 1H), 7.50 (d, J=8.7 Hz, 2H), 8.04 (d, J=9.0 Hz, 2H).

Step 3: 4-Amino-N-(2,5-dichlorophenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(286 mg, 0.87 mmol) using iron powder (245 mg, 4.39 mmol) and ammoniumchloride (470 mg, 8.79 mmol) in a mixture of ethanol and water (3:1, 16mL) as per the procedure described in step 3 of Intermediate 1 to obtain197 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 5.51(s, 2H), 6.32 (d, J=8.1 Hz, 2H), 6.98 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.7Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.58 (s, 1H); APCI-MS (m/z) 295 (M+H)⁺.

Intermediate 6 4-Amino-N-(2-chlorophenyl)-N-methylbenzamide

Step 1: N-(2-Chlorophenyl)-4-nitrobenzamide

To a stirred solution of 2-chloroaniline (3.0 g, 23.51 mmol) indichloromethane (60 mL) was added triethylamine (9.8 mL, 70.54 mmol) andcooled to 0° C. 4-Nitrobenzoyl chloride (4.36 g, 23.51 mmol) was addedand the resulting mixture was stirred overnight at RT. The reaction wasdiluted with dichloromethane (50 mL), washed with water (50 mL) andbrine (50 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated to give an oily residue which wastriturated with diethyl ether. The solid obtained was filtered andwashed with diethyl ether (50 mL) to yield 3.8 g of the desired product.¹H NMR (300 MHz, DMSO-d₆) δ 7.31-7.43 (m, 2H), 7.58 (d, J=7.5 Hz, 2H),8.20 (d, J=8.7 Hz, 2H), 8.38 (d, J=9.0 Hz, 2H), 10.45 (s, 1H).

Step 2: N-(2-Chlorophenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(2.0 g, 7.33 mmol) with methyl iodide (596 μL, 9.53 mmol) using sodiumhydride (60% w/w, 352 mg, 8.80 mmol) in anhydrous DMF (20 mL) as per theprocedure described in step 2 of Intermediate 1 to yield 2.1 g of theproduct. ¹H NMR (300 MHz, CDCl₃) δ 3.42 (s, 3H), 7.11-7.26 (m, 3H), 7.36(d, J=7.2 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 8.02 (d, J=9.0 Hz, 2H).

Step 3: 4-Amino-N-(2-chlorophenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(2.05 g, 7.05 mmol) using iron powder (1.2 g, 21.15 mmol) and ammoniumchloride (3.76 g, 70.51 mmol) in a mixture of ethanol and water (1:1, 50mL) as per the procedure described in step 3 of Intermediate 1 to obtain1.5 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 5.45 (s,2H), 6.28 (d, J=7.8 Hz, 2H), 6.96 (d, J=7.5 Hz, 2H), 7.28-7.33 (m, 3H),7.46 (d, J=6.3 Hz, 1H).

Intermediate 7 2-(4-(1,1-Difluoro-2-methoxyethyl)phenyl)acetic acid

Step 1: Ethyl (4-bromophenyl)(difluoro)acetate

The titled compound was prepared by the reaction of1-bromo-4-iodobenzene (1.0 g, 3.55 mmol) with ethyl bromodifluoroacetate (1.43 g, 7.06 mmol) using copper powder (903 mg, 14.2mmol) in DMSO (10 mL) as per the procedure described in Intermediate 2to yield 623 mg of the product. ¹H NMR (300 MHz, CDCl₃) δ 1.30 (t, J=7.2Hz, 3H), 4.29 (q, J=7.2 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4Hz, 2H).

Step 2: 2-(4-Bromophenyl)-2,2-difluoroethanol

To a stirred solution of Step 1 intermediate (206 mg, 0.73 mmol) inethanol (4.0 mL) at −10° C. was added calcium chloride (25 mg, 0.22mmol) followed by sodium borohydride (70 mg, 1.84 mmol). The resultingmixture was stirred at RT for 2 h. The reaction was quenched withaqueous saturated sodium bicarbonate solution (10 mL) and extracted withethyl acetate (40 mL×2). The combined organic layers were washed withbrine (50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography to yield 176 mg of the titledproduct. 1H NMR (300 MHz, CDCl₃) δ 3.95 (t, J=13.2 Hz, 2H), 7.40 (d,J=8.4 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H).

Step 3: 1-Bromo-4-(1,1-difluoro-2-methoxyethyl)benzene

The titled compound was prepared by the reaction of Step 2 intermediate(170 mg, 0.71 mmol) with methyl iodide (68 μL, 1.07 mmol) using sodiumhydride (60% w/w, 37 mg, 0.93 mmol) in anhydrous DMF (20 mL) as per theprocedure described in step 2 of Intermediate 1 to yield 141 mg of theproduct. ¹H NMR (300 MHz, CDCl₃) δ 3.42 (s, 3H), 3.78 (t, J=12.6 Hz,2H), 7.39 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H).

Step 4: tert-Butyl 2-(4-(1,1-difluoro-2-methoxyethyl)phenyl)acetate

The titled compound was prepared by the reaction of Step 3 intermediate(506 mg, 2.01 mmol) with tert-butyl acetate (272 μL, 2.01 mmol) in thepresence of n-butyl lithium (1.51 mL, 2.41 mmol), tri-tert-butylphosphonium tetrafluoroborate (58 mg, 0.20 mmol) andbis(dibenzylidene)acetone palladium (0) (58 mg, 0.10 mmol) usingdicyclohexylamine (782 μL, 2.41 mmol) in toluene (10 mL) as per theprocedure described in Step 3 of Intermediate 3 to yield 398 mg of theproduct. ¹H NMR (300 MHz, CDCl₃) δ 1.44 (s, 9H), 3.43 (s, 3H), 3.55 (s,2H), 3.79 (t, J=13.2 Hz, 2H), 7.34 (d, J=7.8 Hz, 2H), 7.46 (d, J=8.4 Hz,2H).

Step 5: 2-(4-(1,1-Difluoro-2-methoxyethyl)phenyl)acetic acid

The titled compound was prepared by the reaction of Step 4 intermediate(386 mg, 1.38 mmol) with trifluoroacetic acid (3.0 mL) indichloromethane (6.0 mL) as per the procedure described in Step 4 ofIntermediate 3 to afford 161 mg of the product. ¹H NMR (300 MHz,DMSO-d₆) δ 3.31 (s, 3H), 3.62 (s, 2H), 3.86 (t, J=14.1 Hz, 2H), 7.35 (d,J=7.8 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 12.41 (br s, 1H).

Intermediate 8 4-Amino-N-(3,5-dimethylphenyl)-N-methylbenzamide

Step 1: N-(3,5-Dimethylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of 3,5-dimethylaniline(2.0 g, 16.50 mmol) and 4-nitrobenzoyl chloride (3.06 mg, 16.50 mmol)using N,N′-diisopropylethylamine (5.7 mL, 33.00 mmol) in dichloromethane(40 mL) as per the procedure described in Step 1 of Intermediate 1 toyield 3.4 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.27 (s, 6H),6.78 (s, 1H), 7.40 (s, 2H), 8.16 (d, J=8.1 Hz, 2H), 8.36 (d, J=8.7 Hz,2H), 10.41 (s, 1H).

Step 2: N-(3,5-Dimethylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(2.0 g, 7.39 mmol) with methyl iodide (600 μL, 9.61 mmol) using sodiumhydride (60% w/w, 390 mg, 9.61 mmol) in anhydrous DMF (15 mL) as per theprocedure described in step 2 of Intermediate 1 to yield 1.9 g of theproduct. ¹H NMR (300 MHz, CDCl₃) δ 2.19 (s, 6H), 3.47 (s, 3H), 6.63 (s,2H), 6.80 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.7 Hz, 2H).

Step 3: 4-Amino-N-(3,5-dimethylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(1.9 g, 6.68 mmol) using iron powder (1.2 g, 20.04 mmol) and ammoniumchloride (3.6 g, 66.82 mmol) in a mixture of ethanol and water (5:1, 40mL) as per the procedure described in step 3 of Intermediate 1 to obtain1.6 g of the product. ¹H NMR (300 MHz, CDCl₃) δ 2.21 (s, 6H), 3.42 (s,3H), 6.46 (d, J=7.2 Hz, 2H), 6.66 (s, 2H), 6.77 (s, 1H), 7.17 (d, J=8.4Hz, 2H).

Intermediate 94-Amino-N-(2′-fluoro-5-methylbiphenyl-3-yl)-N-methylbenzamide

Step 1: 2′-Fluoro-5-methylbiphenyl-3-amine

To a stirred solution of 3-bromo-5-methylaniline (504 mg, 2.68 mmol),2-fluorophenyl boronic acid (413 mg, 2.95 mmol) and potassium carbonate(1.1 g, 8.04 mmol) in a mixture of DMF (15 mL) and water (5.0 mL) wasadded tetrakis(triphenylphosphine)palladium(0) (155 mg, 0.13 mmol) atRT. The reaction mixture was evacuated, flushed with nitrogen andstirred at 80° C. for 16 h. The reaction mixture was cooled to RT,diluted with ethyl acetate (30 mL), washed with water (30 mL) and brine(30 mL). The organic layer was concentrated under reduced pressure andpurified by silica gel column chromatography to obtain 400 mg of thetitled product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.18 (s, 3H), 5.07 (s, 2H),6.38-6.51 (m, 3H), 7.18-7.25 (m, 2H), 7.30-7.41 (m, 2H); APCI-MS (m/z)202 (M+H)⁺.

Step 2: N-(2′-Fluoro-5-methylbiphenyl-3-yl)-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(375 mg, 1.86 mmol) and 4-nitrobenzoyl chloride (380 mg, 2.05 mmol)using triethylamine (510 μL, 3.72 mmol) in dichloromethane (10 mL) asper the procedure described in Step 1 of Intermediate 1 to yield 500 mgof the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.36 (s, 3H), 7.12 (s, 1H),7.26-7.33 (m, 2H), 7.40-7.52 (m, 2H), 7.66 (s, 1H), 7.78 (s, 1H), 8.08(d, J=8.4 Hz, 2H), 8.35 (d, J=8.4 Hz, 2H), 10.58 (s, 1H).

Step 3: N-(2′-Fluoro-5-methylbiphenyl-3-yl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 2 intermediate(500 mg, 1.42 mmol) with methyl iodide (133 μL, 2.14 mmol) using sodiumhydride (60% w/w, 85 mg, 2.14 mmol) in anhydrous DMF (10 mL) as per theprocedure described in step 2 of Intermediate 1 to yield 430 mg of theproduct. The product obtained was used as such without characterization.

Step 4: 4-Amino-N-(2′-fluoro-5-methylbiphenyl-3-yl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 3 intermediate(405 mg, 1.11 mmol) using iron powder (310 mg, 5.55 mmol) and ammoniumchloride (588 mg, 11.00 mmol) in a mixture of ethanol and water (2:1, 15mL) as per the procedure described in step 3 of Intermediate 1 to obtain305 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H), 3.34(s, 3H), 5.45 (s, 2H), 6.32 (d, J=8.4 Hz, 2H), 7.01 (d, J=7.8 Hz, 4H),7.14 (s, 1H), 7.23-7.40 (m, 4H); ESI-MS (m/z) 337 (M+H)⁺.

Intermediate 104-Amino-N-(3-chlorophenyl)-N-(2,2,2-trifluoroethyl)benzamide

Step 1: N-(3-Chlorophenyl)-2,2,2-trifluoroacetamide

To a cooled (□78° C.), stirred solution of 3-chloroaniline (2.0 g, 15.68mmol) and triethylamine (2.2 mL, 15.68 mmol) in dichloromethane (40 mL)was added trifluoroacetic anhydride (2.2 mL, 15.68 mmol). The mixturewas warmed to RT and stirred for 1 h. The mixture was diluted withdichloromethane (200 mL) and washed with water (100 mL) followed bybrine (100 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography to yield 2.29g of the titled product. ¹H NMR (300 MHz, DMSO-d₆) δ 7.30 (d, J=7.8 Hz,1H), 7.44 (t, J=8.4 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.80 (s, 1H), 11.43(s, 1H).

Step 2: 3-Chloro-N-(2,2,2-trifluoroethyl)aniline

To a stirred solution of Step 1 intermediate (2.2 g, 9.84 mmol) in THF(75 mL) at 0° C. was added borane dimethylsulfide complex (2.05 mL,21.65 mmol). The reaction mixture was allowed to attain RT and thenheated to reflux for 2 h. The mixture was cooled to 0° C., quenched withmethanol (5 mL) and stirred at RT for 30 min. The reaction mixture waspoured into water (20 mL) and extracted with ethyl acetate (50 mL×2).The combined organic layers were washed with brine (50 mL) andconcentrated under reduced pressure to yield 1.7 g of the product. ¹HNMR (300 MHz, DMSO-d₆) δ 3.91-4.03 (m, 2H), 6.49-6.53 (m, 1H), 6.61-6.69(m, 2H), 6.77 (s, 1H), 7.10 (t, J=7.8 Hz, 1H).

Step 3: N-(3-Chlorophenyl)-4-nitro-N-(2,2,2-trifluoroethyl)benzamide

The titled compound was prepared by the reaction of Step 2 intermediate(1.8 g, 8.58 mmol) with 4-nitrobenzoyl chloride (1.6 g, 8.58 mmol) usingtriethylamine (3.6 mL, 25.76 mmol) in dichloromethane (30 mL) as per theprocedure described in Step 1 of Intermediate 1 to yield 1.8 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 4.78 (q, J=9.3 Hz, 2H), 7.14-7.17(m, 1H), 7.26 (d, J=6.6 Hz, 2H), 7.53 (s, 1H), 7.56 (d, J=9.0 Hz, 2H),8.08 (d, J=8.7 Hz, 2H).

Step 4: 4-Amino-N-(3-chlorophenyl)-N-(2,2,2-trifluoroethyl)benzamide

The titled compound was prepared by the reduction of Step 3 intermediate(1.8 g, 5.24 mmol) using iron powder (880 mg, 15.74 mmol) and ammoniumchloride (2.8 g, 52.49 mmol) in a mixture of ethanol and water (5:1, 60mL) as per the procedure described in step 3 of Intermediate 1 to obtain1.43 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 4.68 (q, J=9.3 Hz,2H), 5.62 (s, 2H), 6.32 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 7.07(s, 1H), 7.26-7.32 (m, 3H).

Intermediate 11(R)-4-Amino-N-(1-(4-chlorophenyl)ethyl)-N-methylbenzamide

Step 1: (R)—N-(1-(4-Chlorophenyl)ethyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of(R)-(+)-α-methylbenzylamine (507 mg, 3.25 mmol) with 4-nitrobenzoylchloride (725 mg, 3.90 mmol) using triethylamine (988 mg, 9.77 mmol) andDMAP (39 mg, 0.32 mmol) in dichloromethane (5.0 mL) as per the proceduredescribed in Step 1 of Intermediate 1 to yield 603 mg of the product. ¹HNMR (300 MHz, CDCl₃) δ 1.60 (d, J=7.5 Hz, 3H), 5.27 (t, J=8.7 Hz, 1H),6.56 (s, 1H), 7.25-7.32 (m, 4H), 7.91 (d, J=8.1 Hz, 2H), 8.24 (d, J=8.7Hz, 2H); ESI-MS (m/z) 290 (M+H)⁺.

Step 2: (R)—N-(1-(4-Chlorophenyl)ethyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(253 mg, 0.83 mmol) with methyl iodide (176 mg, 1.24 mmol) using sodiumhydride (60% w/w, 43 mg, 1.07 mmol) in anhydrous DMF (5.0 mL) as per theprocedure described in step 2 of Intermediate 1 to yield 231 mg of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 1.55 (s, 3H), 2.70 (s, 3H), 4.73,5.87 (br s, 1H, rotamer), 7.29 (s, 1H), 7.43 (s, 3H), 7.73 (d, J=7.2 Hz,2H), 8.29 (d, J=7.2 Hz, 2H); ESI-MS (m/z) 317 (M−H)⁺.

Step 3: (R)-4-Amino-N-(1-(4-chlorophenyl)ethyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(201 mg, 0.63 mmol) using iron powder (106 mg, 1.90 mmol) and ammoniumchloride (339 mg, 6.33 mmol) in a mixture of ethanol and water (3:1, 10mL) as per the procedure described in step 3 of Intermediate 1 to obtain131 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.54 (d, J=7.5 Hz,3H), 2.61 (s, 3H), 5.50 (s, 3H), 6.54 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.1Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H); ESI-MS (m/z)289 (M+H)⁺.

Intermediate 12(S)-4-Amino-N-(1-(4-chlorophenyl)ethyl)-N-methylbenzamide

Step 1: (S)—N-(1-(4-Chlorophenyl)ethyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of(S)-4-chloro-α-methylbenzylamine (503 mg, 3.23 mmol) with 4-nitrobenzoylchloride (599 mg, 3.23 mmol) using triethylamine (1.3 mL, 9.69 mmol) andDMAP (39 mg, 0.32 mmol) in dichloromethane (10 mL) as per the proceduredescribed in Step 1 of Intermediate 1 to yield 511 mg of the product. ¹HNMR (300 MHz, DMSO-d₆) δ 1.47 (d, J=7.2 Hz, 3H), 5.12-5.19 (m, 1H),7.38-7.42 (m, 4H), 8.10 (d, J=8.1 Hz, 2H), 8.31 (d, J=8.1 Hz, 2H), 9.18(d, J=7.8 Hz, 1H); APCI-MS (m/z) 305 (M+H)⁺.

Step 2: (S)—N-(1-(4-Chlorophenyl)ethyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(253 mg, 0.83 mmol) with methyl iodide (176 mg, 1.24 mmol) using sodiumhydride (60% w/w, 43 mg, 1.07 mmol) in anhydrous DMF (5.0 mL) as per theprocedure described in step 2 of Intermediate 1 to yield 214 mg of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 1.53 (d, J=7.2 Hz, 3H), 2.53 (s,3H), 5.81-5.85 (m, 1H), 7.25-7.30 (m, 1H), 7.38-7.43 (m, 3H), 7.71 (d,J=7.8 Hz, 2H), 8.26 (d, J=8.4 Hz, 2H); APCI-MS (m/z) 319 (M+H)⁺.

Step 3: (S)-4-Amino-N-(1-(4-chlorophenyl)ethyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(201 mg, 0.63 mmol) using iron powder (106 mg, 1.90 mmol) and ammoniumchloride (339 mg, 6.33 mmol) in a mixture of ethanol and water (3:1, 10mL) as per the procedure described in step 3 of Intermediate 1 to obtain131 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.50 (d, J=6.6 Hz,3H), 2.60 (s, 3H), 5.44-5.48 (m, 3H), 6.52 (d, J=8.4 Hz, 2H), 7.13 (d,J=8.4 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H).

Intermediate 13(R)-4-Amino-N-((4-chlorophenyl)(cyclopropyl)methyl)-N-methylbenzamide

Step 1: (4-Chlorophenyl)(cyclopropyl)methanone

To a stirred solution of cyclopropylcarbonitrile (607 mg, 9.04 mmol) inanhydrous diethyl ether (25 mL) was slowly added4-chlorophenylmagnessium bromide (1M, 11 mL, 11.76 mmol) at 0° C. Thereaction mixture was gradually warmed up to RT in duration of 2 h andcontinued to stir for another 6 h at RT. To that mixture were added 1NHCl (11 mL) and THF (11 mL) and continued to stir overnight at RT. Thereaction mixture was cooled to 0° C. and quenched with saturated aqueoussolution of ammonium chloride (50 mL) and ethyl acetate (50 mL). Thelayers were separated and the aqueous layer was extracted with ethylacetate (50 mL×2). The combined organic layers were washed with brine(50 mL) and concentrated under reduced pressure. The residue obtainedwas purified by silica gel column chromatography to yield 705 mg of thetitled product. ¹H NMR (300 MHz, CDCl₃) δ 1.03-1.09 (m, 2H), 1.22-1.28(m, 2H), 2.57-2.67 (m, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.4 Hz,2H).

Step 2:N—((R)-(4-Chlorophenyl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide

To a stirred solution of Step 1 intermediate (705 mg, 3.90 mmol) in THF(10 mL) were added titanium (VI) isopropoxide (1.7 mL, 8.19 mmol) and(R)-(+)-2-methyl-2-propanesulfinamide (520 mg, 4.29 mmol) at RT underinert atmosphere. The reaction mixture was stirred at 70° C. for 18 h.The mixture was cooled to 0° C. and added sodium borohydride (474 mg,12.4 mmol) and stirred at RT for 3 h. The reaction was quenched withmethanol (20 mL) at 0° C. The precipitated solid was filtered off andwashed with ethyl acetate (50 mL×2). The combined filtrates were washedwith water (40 mL), dried over anhydrous sodium sulfate, filtered andconcentrated. The residue obtained was purified by silica gel columnchromatography to afford 459 mg of the titled compound. ¹H NMR (300 MHz,CDCl₃) δ 0.16-0.24 (m, 1H), 0.33-0.39 (m, 1H), 0.43-0.53 (m, 1H),0.55-0.67 (m, 1H), 0.68-0.77 (m, 1H), 3.55-5.28 (m, 1H, NH, rotamer),7.27-7.31 (m, 4H)), 7.32 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H);ESI-MS (m/z) 286 (M+H)⁺.

Step 3: ((R)-(4-Chlorophenyl)(cyclopropyl)methanamine hydrochloride

To an ice cold solution of Step 2 intermediate (454 mg, 1.58 mmol) indiethyl ether (10 mL) was added 4 M HCl in 1,4-dioxane (4.0 mL, 15.9mmol) at RT. The resulting mixture was stirred at 0° C. for 1 h. Thesolvent was evaporated under reduced pressure and the residue thusobtained was dried under high vacuum to yield 340 mg of the titledcompound. ¹H NMR (300 MHz, DMSO-d₆) δ 0.34-0.37 (m, 1H), 0.45-0.50 (m,1H), 0.59-0.65 (m, 2H), 1.27-1.31 (m, 1H), 3.59 (br s, 1H), 7.48 (d,J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H).

Step 4: (R)—N-((4-Chlorophenyl)(cyclopropyl)methyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 3 intermediate(327 mg, 1.49 mmol) with 4-nitrobenzoylchloride (305 mg, 1.64 mmol) inthe presence triethylamine (625 μL, 4.49 mmol) in dichloromethane (10mL) as per the procedure described in step 1 of Intermediate 1 to yield315 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 0.42-0.45 (m, 2H),0.53-0.59 (m, 2H), 1.27-1.34 (m, 1H), 4.35 (t, J=8.7 Hz, 1H), 7.40 (d,J=8.1 Hz, 2H), 7.48 (d, J=7.5 Hz, 2H), 8.11 (d, J=8.7 Hz, 2H), 8.32 (d,J=8.7 Hz, 2H), 9.38 (d, J=7.8 Hz, 1H); ESI-MS (m/z) 331 (M+H)⁺.

Step 5:(R)—N-((4-Chlorophenyl)(cyclopropyl)methyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 4 intermediate(307 mg, 0.92 mmol) with methyl iodide (87 μL, 1.37 mmol) using sodiumhydride (60% w/w, 48 mg, 2.02 mmol) in anhydrous DMF (10 mL) as per theprocedure described in step 2 of Intermediate 1 to yield 283 mg of thedesired product. ESI-MS (m/z) 344 (M)⁺.

Step 6:(R)-4-Amino-N-((4-chlorophenyl)(cyclopropyl)methyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 5 intermediate(273 mg, 0.79 mmol) using iron powder (132 mg, 2.37 mmol) and ammoniumchloride (423 mg, 7.91 mmol) in a mixture of ethanol and water (2:1, 12mL) as per the procedure described in step 3 of Intermediate 1 to obtain174 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 0.39 (br s, 1H), 0.57(br s, 2H), 0.79 (br s, 2H), 1.28-1.41 (m, 1H), 2.77 (s, 3H), 5.47 (s,2H), 6.50 (d, J=7.8 Hz, 2H), 7.10 (d, J=7.2 Hz, 2H), 7.44 (s, 4H);ESI-MS (m/z) 315 (M+H)⁺.

Intermediate 14 4-Amino-N-(3,5-dichlorophenyl)-N-methylbenzamide

Step 1: N-(3,5-Dichlorophenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of 3,5-dichloroaniline(2.0 g, 12.42 mmol) with 4-nitrobenzoylchloride (2.42 g, 13.04 mmol) inthe presence of triethylamine (5.2 mL, 37.26 mmol) in dichloromethane(20 mL) as per the procedure described in Step 1 of Intermediate 1 toyield 2.59 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 7.37 (s, 1H),7.89 (s, 2H), 8.17 (d, J=8.7 Hz, 2H), 8.38 (d, J=8.7 Hz, 2H), 10.82 (s,1H).

Step 2: N-(3,5-Dichlorophenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(2.51 g, 8.06 mmol) with methyl iodide (656 μL, 10.48 mmol) using sodiumhydride (60% w/w, 388 mg, 9.68 mmol) in anhydrous DMF (25 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 2.38 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 3.34 (s, 3H), 7.45 (s, 3H), 7.60(d, J=8.7 Hz, 2H), 8.16 (d, J=8.4 Hz, 2H).

Step 3: 4-Amino-N-(3,5-dichlorophenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(2.3 g, 7.07 mmol) using iron powder (1.18 g, 21.21 mmol) and ammoniumchloride (3.77 g, 70.73 mmol) in a mixture of ethanol and water (5:1, 60mL) as per the procedure described in Step 3 of Intermediate 1 to obtain1.75 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 3.29 (s, 3H), 5.55(s, 2H), 6.35 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 7.20 (s, 2H),7.34 (s, 1H).

Intermediate 15 4-Amino-N-(3-chloro-5-fluorophenyl)-N-methylbenzamide

Step 1: N-(3-Chloro-5-fluorophenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of3-chloro-5-fluoroaniline (1.0 g, 6.86 mmol) with 4-nitrobenzoylchloride(1.27 g, 6.86 mmol) in the presence of triethylamine (1.9 mL, 13.73mmol) in dichloromethane (20 mL) as per the procedure described in Step1 of Intermediate 1 to yield 933 mg of the product. ¹H NMR (300 MHz,DMSO-d₆) δ 7.21 (d, J=8.1 Hz, 1H), 7.65-7.76 (m, 2H), 8.17 (d, J=9.0 Hz,2H), 8.40 (d, J=9.0 Hz, 2H), 10.86 (s, 1H).

Step 2: N-(3-Chloro-5-fluorophenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(924 mg, 3.13 mmol) with methyl iodide (238 μL, 3.76 mmol) using sodiumhydride (60% w/w, 150 mg, 3.76 mmol) in anhydrous DMF (10 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 1.04 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 3.33 (s, 3H), 7.24-7.35 (m, 3H),7.60 (d, J=8.4 Hz, 2H), 8.16 (d, J=8.4 Hz, 2H).

Step 3: 4-Amino-N-(3-chloro-5-fluorophenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(1.03 g, 3.33 mmol) using iron powder (559 mg, 10.00 mmol) and ammoniumchloride (1.78 g, 33.36 mmol) in a mixture of ethanol and water (5:1, 30mL) as per the procedure described in Step 3 of Intermediate 1 to yield732 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 3.31 (s, 3H), 5.57(s, 2H), 6.37 (d, J=8.4 Hz, 2H), 6.98-7.10 (m, 4H), 7.20 (d, J=8.1 Hz,1H).

Intermediate 16 4-Amino-N-(2-chloro-4-methylphenyl)-N-methylbenzamide

Step 1: N-(2-Chloro-4-methylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of2-chloro-4-methylaniline (1.0 g, 7.06 mmol) with 4-nitrobenzoylchloride(1.3 g, 7.06 mmol) in the presence of triethylamine (3.0 mL, 21.18 mmol)in dichloromethane (20 mL) as per the procedure described in Step 1 ofIntermediate 1 to yield 2.03 g of the product. ¹H NMR (300 MHz, DMSO-d₆)δ 2.33 (s, 3H), 7.20 (d, J=7.8 Hz, 1H), 7.39-7.45 (m, 2H), 8.20 (d,J=8.1 Hz, 2H), 8.36 (d, J=9.0 Hz, 2H), 10.43 (s, 1H).

Step 2: N-(2-Chloro-4-methylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(2.0 g, 6.87 mmol) with methyl iodide (516 μL, 8.25 mmol) using sodiumhydride (60% w/w, 330 mg, 8.25 mmol) in anhydrous DMF (20 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 2.04 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 2.21 (s, 3H), 3.26 (s, 3H), 7.11(d, J=8.1 Hz, 1H), 7.27 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.54 (d, J=8.7Hz, 2H), 8.07 (d, J=8.4 Hz, 2H).

Step 3: 4-Amino-N-(2-chloro-4-methylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(2.01 g, 6.59 mmol) using iron powder (1.1 g, 19.78 mmol) and ammoniumchloride (3.52 g, 65.96 mmol) in a mixture of ethanol and water (5:1, 30mL) as per the procedure described in Step 3 of Intermediate 1 to obtain1.63 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.23 (s, 3H), 3.13(s, 3H), 5.42 (s, 2H), 6.26 (d, J=7.8 Hz, 2H), 6.94 (d, J=7.8 Hz, 2H),7.06 (d, J=8.4 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.26 (s, 1H).

Intermediate 17 4-Amino-N-(4-chloro-2-methylphenyl)-N-methylbenzamide

Step 1: N-(4-Chloro-2-methylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of4-chloro-2-methylaniline (1.0 g, 7.06 mmol) with 4-nitrobenzoylchloride(1.3 g, 7.06 mmol) in a mixture of pyridine and dichloromethane (1:1, 20mL) as per the procedure described in Step 1 of Intermediate 1 to yield2.03 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.22 (s, 3H), 7.28(d, J=8.4 Hz, 1H), 7.38 (d, J=6.6 Hz, 2H), 8.17 (d, J=8.7 Hz, 2H), 8.35(d, J=8.7 Hz, 2H), 10.24 (s, 1H).

Step 2: N-(4-Chloro-2-methylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step intermediate(2.0 g, 6.87 mmol) with methyl iodide (560 μL, 8.94 mmol) using sodiumhydride (60% w/w, 357 mg, 8.94 mmol) in anhydrous DMF (20 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 2.1 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 2.18 (s, 3H), 3.26 (s, 3H), 7.17(d, J=8.1 Hz, 1H), 7.31 (d, J=8.7 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 8.06(d, J=8.7 Hz, 2H).

Step 3: 4-Amino-N-(4-chloro-2-methylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(2.1 g, 6.89 mmol) using iron powder (1.15 g, 20.63 mmol) and ammoniumchloride (3.68 g, 68.91 mmol) in a mixture of ethanol and water (5:1, 30mL) as per the procedure described in Step 3 of Intermediate 1 to obtain1.7 g of the product. ¹H NMR (300 MHz, DMSO-d₆): δ 2.08 (s, 3H), 3.15(s, 3H), 5.46 (s, 2H), 6.28-6.33 (m, 2H), 6.89-6.94 (m, 2H), 7.15-7.20(m, 2H), 7.28 (s, 1H).

Intermediate 18 4-Amino-N-(2,4-dichlorophenyl)-N-methylbenzamide

Step 1: N-(2,4-Dichlorophenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of 2,4-dichloroaniline(2.0 g, 12.42 mmol) with 4-nitrobenzoylchloride (2.4 g, 13.04 mmol) in amixture of pyridine and dichloromethane (1:1, 20 mL) as per theprocedure described in Step 1 of Intermediate 1 to yield 2.9 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 7.50 (d, J=8.1 Hz, 1H), 7.63 (d,J=8.7 Hz, 1H), 7.76 (s, 1H), 8.20 (d, J=8.4 Hz, 2H), 8.38 (d, J=8.7 Hz,2H), 10.51 (s, 1H).

Step 2: N-(2,4-Dichlorophenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(2.5 g, 8.03 mmol) with methyl iodide (605 μL, 9.64 mmol) using sodiumhydride (60% w/w, 386 mg, 9.64 mmol) in anhydrous DMF (20 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 2.4 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 3.28 (s, 3H), 7.41 (d, J=8.4 Hz,1H), 7.53 (d, J=8.1 Hz, 2H), 7.64 (d, J=7.5 Hz, 2H), 8.10 (d, J=9.0 Hz,2H).

Step 3: 4-Amino-N-(2,4-dichlorophenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(2.4 g, 7.65 mmol) using iron powder (1.3 g, 22.95 mmol) and ammoniumchloride (4.03 g, 76.51 mmol) in a mixture of ethanol and water (5:1, 30mL) as per the procedure described in Step 3 of Intermediate 1 to obtain1.9 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 5.50 (s,2H), 6.31 (d, J=7.8 Hz, 2H), 6.96 (d, J=7.5 Hz, 2H), 7.39 (s, 2H), 7.65(s, 1H).

Intermediate 19 4-Amino-N-(3-chloro-2-fluorophenyl)-N-methylbenzamide

Step 1: N-(3-Chloro-2-fluorophenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of3-chloro-2-fluoroaniline (2.0 g, 13.73 mmol) with 4-nitrobenzoylchloride(2.54 g, 13.73 mmol) in a mixture of pyridine and dichloromethane (1:1,20 mL) as per the procedure described in Step 1 of Intermediate 1 toyield 2.1 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (t, J=6.9Hz, 2H), 8.21 (d, J=8.7 Hz, 2H), 8.38 (d, J=8.7 Hz, 2H), 8.50-8.54 (m,1H), 10.73 (s, 1H); ESI-MS (m/z) 293 (M−H)⁻.

Step 2: N-(3-Chloro-2-fluorophenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(2.0 g, 4.78 mmol) with methyl iodide (523 μL, 8.14 mmol) using sodiumhydride (60% w/w, 325 mg, 8.14 mmol) in anhydrous DMF (20 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 1.4 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆): δ 3.32 (s, 3H), 7.16-7.21 (m, 1H),7.45-7.53 (m, 4H), 8.10-8.16 (m, 2H).

Step 3: 4-Amino-N-(3-chloro-2-fluorophenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(1.3 g, 4.21 mmol) using iron powder (705 mg, 12.63 mmol) and ammoniumchloride (2.25 g, 42.11 mmol) in a mixture of ethanol and water (5:1, 60mL) as per the procedure described in Step 3 of Intermediate 1 to obtain890 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 3.24 (s, 3H), 5.53(s, 2H), 6.32 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 7.18 (t, J=8.4Hz, 1H), 7.33-7.46 (m, 2H).

Intermediate 20 4-Amino-N-(2-chloro-5-methylphenyl)-N-methylbenzamide

Step 1: N-(2-Chloro-5-methylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of2-chloro-5-methylaniline (2.0 g, 14.12 mmol) with 4-nitrobenzoylchloride(2.62 g, 14.12 mmol) in a mixture of pyridine and dichloromethane (1:1,20 mL) as per the procedure described in Step 1 of Intermediate 1 toyield 3.4 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H),7.13 (d, J=7.2 Hz, 1H), 7.37-7.45 (m, 2H), 8.18 (d, J=8.7 Hz, 2H), 8.36(d, J=8.7 Hz, 2H), 10.39 (s, 1H); APCI-MS (m/z) 289 (M−H)⁻.

Step 2: N-(2-Chloro-5-methylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(2.0 g, 6.87 mmol) with methyl iodide (560 μL, 8.94 mmol) using sodiumhydride (60% w/w, 358 mg, 8.94 mmol) in anhydrous DMF (20 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 1.7 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 2.21 (s, 3H), 3.28 (s, 3H), 7.09(d, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.43 (s, 1H), 7.54 (d, J=8.4Hz, 2H), 8.06 (d, J=9.0 Hz, 2H).

Step 3: 4-Amino-N-(2-chloro-5-methylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(1.6 g, 5.25 mmol) using iron powder (880 mg, 15.75 mmol) and ammoniumchloride (2.8 g, 52.50 mmol) in a mixture of ethanol and water (5:1, 60mL) as per the procedure described in Step 3 of Intermediate 1 to obtain1.2 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.22 (s, 3H), 3.16 (s,3H), 5.46 (s, 2H), 6.28 (d, J=7.8 Hz, 2H), 6.98 (d, J=7.8 Hz, 3H), 7.18(s, 1H), 7.32 (d, J=8.4 Hz, 1H).

Intermediate 21 4-Amino-N-(2-fluoro-5-methylphenyl)-N-methylbenzamide

Step 1: N-(2-Fluoro-5-methylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of2-fluoro-5-methylaniline (1.0 g, 7.99 mmol) with 4-nitrobenzoylchloride(1.48 g, 7.99 mmol) in a mixture of pyridine and dichloromethane (1:1,20 mL) as per the procedure described in Step 1 of Intermediate 1 toyield 1.7 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.30 (s, 3H),7.08-7.24 (m, 2H), 7.42 (d, J=6.0 Hz, 1H), 8.18 (d, J=9.0 Hz, 2H), 8.36(d, J=9.0 Hz, 2H), 10.42 (s, 1H).

Step 2: N-(2-Fluoro-5-methylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(1.64 g, 6.00 mmol) with methyl iodide (457 μL, 7.20 mmol) using sodiumhydride (60% w/w, 288 mg, 7.20 mmol) in anhydrous DMF (10 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 1.8 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 2.21 (s, 3H), 3.33 (s, 3H),7.01-7.09 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 2H), 8.10(d, J=8.4 Hz, 2H).

Step 3: 4-Amino-N-(2-fluoro-5-methylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(1.74 g, 6.03 mmol) using iron powder (1.01 g, 18.10 mmol) and ammoniumchloride (3.22 g, 60.36 mmol) in a mixture of ethanol and water (5:1, 60mL) as per the procedure described in Step 3 of Intermediate 1 to obtain1.4 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.22 (s, 3H), 3.21 (s,3H), 5.46 (s, 2H), 6.30 (d, J=8.1 Hz, 2H), 6.95-7.05 (m, 4H), 7.16 (d,J=7.8 Hz, 1H); APCI-MS (m/z) 260 (M+H)⁺.

Intermediate 22 4-Amino-N-(2-chloro-6-methylphenyl)-N-methylbenzamide

Step 1: N-(2-Chloro-6-methylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of2-chloro-6-methylaniline (502 mg, 3.54 mmol) with 4-nitrobenzoylchloride(657 mg, 3.54 mmol) in a mixture of pyridine and dichloromethane (1:2,15 mL) as per the procedure described in Step 1 of Intermediate 1 toyield 751 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.24 (s, 3H),7.28-7.33 (m, 2H), 7.42 (d, J=6.0 Hz, 1H), 8.22 (d, J=8.7 Hz, 2H), 8.40(d, J=8.7 Hz, 2H), 10.40 (s, 1H); APCI-MS (m/z) 291 (M+H)⁺.

Step 2: N-(2-Chloro-6-methylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(742 mg, 2.55 mmol) with methyl iodide (191 μL, 3.06 mmol) using sodiumhydride (60% w/w, 122 mg, 3.06 mmol) in anhydrous DMF (15 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 620 mg of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 2.30 (s, 3H), 3.23 (s, 3H),7.18-7.23 (m, 2H), 7.26-7.30 (m, 1H), 7.52 (d, J=9.0 Hz, 2H), 8.06 (d,J=8.7 Hz, 2H); APCI-MS (m/z) 305 (M+H)⁺.

Step 3: 4-Amino-N-(2-chloro-6-methylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(610 mg, 2.00 mmol) using iron powder (335 mg, 6.00 mmol) and ammoniumchloride (1.06 g, 20.0 mmol) in a mixture of ethanol and water (5:1, 30mL) as per the procedure described in Step 3 of Intermediate 1 to obtain481 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.14 (s, 3H), 3.10(s, 3H), 5.46 (s, 2H), 6.26 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H),7.18 (d, J=5.4 Hz, 2H), 7.30-7.34 (m, 1H); APCI-MS (m/z) 275 (M+H)⁺.

Intermediate 23 4-Amino-N-mesityl-N-methylbenzamide

Step 1: N-Mesityl-4-nitrobenzamide

The titled compound was prepared by the reaction of2,4,6-trimethylaniline (503 mg, 3.72 mmol) with 4-nitrobenzoylchloride(650 mg, 3.72 mmol) in a mixture of pyridine and dichloromethane (1:2,15 mL) as per the procedure described in Step 1 of Intermediate 1 toyield 936 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.14 (s, 6H),2.25 (s, 3H), 6.94 (s, 2H), 8.20 (d, J=8.7 Hz, 2H), 8.37 (d, J=8.7 Hz,2H), 10.02 (s, 1H); APCI-MS (m/z) 285 (M+H)⁺.

Step 2: N-Mesityl-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(923 mg, 3.25 mmol) with methyl iodide (245 μL, 3.90 mmol) using sodiumhydride (60% w/w, 156 mg, 3.85 mmol) in anhydrous DMF (10 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 899 mg of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 2.14 (s, 9H), 3.19 (s, 3H), 6.83(s, 2H), 7.45 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.1 Hz, 2H); APCI-MS (m/z)299 (M+H)⁺.

Step 3: 4-Amino-N-mesityl-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(893 mg, 2.99 mmol) using iron powder (501 mg, 8.98 mmol) and ammoniumchloride (1.6 g, 29.9 mmol) in a mixture of ethanol and water (5:1, 35mL) as per the procedure described in Step 3 of Intermediate 1 to obtain610 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.06 (s, 6H), 2.18(s, 3H), 3.06 (s, 3H), 5.40 (s, 2H), 6.24 (d, J=8.4 Hz, 2H), 6.84 (s,2H), 6.89 (d, J=8.1 Hz, 2H).

Intermediate 244-Amino-N-(2-chloro-4,6-dimethylphenyl)-N-methylbenzamide

Step 1: N-(2-Chloro-4,6-dimethylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of2-chloro-4,6-dimethylaniline (1.0 g, 6.42 mmol) with4-nitrobenzoylchloride (1.19 g, 6.42 mmol) in a mixture of pyridine anddichloromethane (1:2, 20 mL) as per the procedure described in Step 1 ofIntermediate 1 to yield 1.1 g of the product. ¹H NMR (300 MHz, DMSO-d₆)δ 2.19 (s, 3H), 2.31 (s, 3H), 7.12 (s, 1H), 7.25 (s, 1H), 8.21 (d, J=8.7Hz, 2H), 8.38 (d, J=8.7 Hz, 2H), 10.29 (s, 1H); APCI-MS (m/z) 304(M−H)⁻.

Step 2: N-(2-Chloro-4,6-dimethylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(1.00 g, 3.28 mmol) with methyl iodide (246 μL, 3.93 mmol) using sodiumhydride (60% w/w, 158 mg, 3.93 mmol) in anhydrous DMF (15 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 1.0 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 2.18 (s, 3H), 2.25 (s, 3H), 3.20(s, 3H), 7.02 (s, 1H), 7.13 (s, 1H), 7.52 (d, J=8.4 Hz, 2H), 8.08 (d,J=8.7 Hz, 2H); APCI-MS (m/z) 319 (M+H)⁺.

Step 3: 4-Amino-N-(2-chloro-4,6-dimethylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(1.00 g, 3.13 mmol) using iron powder (525 mg, 9.39 mmol) and ammoniumchloride (1.67 g, 31.37 mmol) in a mixture of ethanol and water (5:1, 60mL) as per the procedure described in Step 3 of Intermediate 1 to obtain731 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.09 (s, 3H), 2.21(s, 3H), 3.08 (s, 3H), 5.43 (s, 2H), 6.27 (d, J=8.7 Hz, 2H), 6.92-6.99(m, 3H), 7.15 (s, 1H); APCI-MS (m/z) 289 (M+H)⁺.

Intermediate 254-Amino-N-(2-cyclopropyl-4-methylphenyl)-N-methylbenzamide

Step 1: N-(2-Cyclopropyl-4-methylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of2-cyclopropyl-4-methylaniline (271 mg, 1.84 mmol) with4-nitrobenzoylchloride (341 mg, 1.84 mmol) in a mixture of pyridine anddichloromethane (1:2, 12 mL) as per the procedure described in Step 1 ofIntermediate 1 to yield 421 mg of the product. ¹H NMR (300 MHz, DMSO-d₆)δ 0.56-0.60 (m, 2H), 0.82-0.88 (m, 2H), 1.95-1.99 (m, 1H), 2.26 (s, 3H),6.80 (s, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 8.19 (d,J=8.7 Hz, 2H), 8.34 (d, J=8.7 Hz, 2H), 10.17 (s, 1H).

Step 2: N-(2-Cyclopropyl-4-methylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(411 mg, 1.38 mmol) with methyl iodide (104 μL, 1.66 mmol) using sodiumhydride (60% w/w, 67 mg, 1.66 mmol) in anhydrous DMF (8.0 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 440 mg of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 0.50-0.55 (m, 1H), 0.64-0.69 (m,1H), 0.95-1.02 (m, 2H), 1.82-1.87 (m, 1H), 2.14 (s, 3H), 3.31 (s, 3H),6.55 (s, 1H), 6.85 (d, J=8.7 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.53 (d,J=9.0 Hz, 2H), 8.04 (d, J=8.7 Hz, 2H).

Step 3: 4-Amino-N-(2-cyclopropyl-4-methylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(434 mg, 1.39 mmol) using iron powder (232 mg, 4.17 mmol) and ammoniumchloride (473 mg, 13.98 mmol) in a mixture of ethanol and water (5:1, 12mL) as per the procedure described in Step 3 of Intermediate 1 to obtain320 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 0.57-0.62 (m, 2H),0.84-0.96 (m, 2H), 1.78-1.84 (m, 1H), 2.20 (s, 3H), 3.20 (s, 3H), 5.36(s, 2H), 6.25-6.31 (m, 2H), 6.62 (s, 1H), 6.88-6.93 (m, 2H), 6.95-6.99(m, 2H).

Intermediate 264-Amino-N-(4-chloro-2-fluoro-5-methylphenyl)-N-methylbenzamide

Step 1: N-(4-Chloro-2-fluoro-5-methylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of4-chloro-2-fluoro-5-methylaniline (252 mg, 1.57 mmol) with4-nitrobenzoylchloride (293 mg, 1.57 mmol) in a mixture of pyridine anddichloromethane (1:2, 6.0 mL) as per the procedure described in Step 1of Intermediate 1 to yield 398 mg of the product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.32 (s, 3H), 7.53 (d, J=10.2 Hz, 1H), 7.62 (d, J=8.4 Hz,1H), 8.19 (d, J=9.0 Hz, 2H), 8.37 (d, J=8.7 Hz, 2H), 10.51 (s, 1H).

Step 2: N-(4-Chloro-2-fluoro-5-methylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(391 mg, 1.26 mmol) with methyl iodide (95 μL, 1.51 mmol) using sodiumhydride (60% w/w, 61 mg, 1.51 mmol) in anhydrous DMF (8.0 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 396 mg of theproduct. The intermediate was as such used for the next step withoutcharacterization.

Step 3: 4-Amino-N-(4-chloro-2-fluoro-5-methylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(390 mg, 1.20 mmol) using iron powder (202 mg, 3.62 mmol) and ammoniumchloride (647 mg, 12.08 mmol) in a mixture of ethanol and water (5:1, 12mL) as per the procedure described in Step 3 of Intermediate 1 to obtain260 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.42 (s, 3H), 3.21(s, 3H), 5.49 (s, 2H), 6.34 (d, J=8.1 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H),7.34-7.44 (m, 2H); ESI-MS (m/z) 293 (M+H)⁺.

Intermediate 274-Amino-N-(2-chloro-4-cyclopropylphenyl)-N-methylbenzamide

Step 1: N-(2-Chloro-4-cyclopropylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of2-chloro-4-cyclopropylaniline (252 mg, 1.50 mmol) with4-nitrobenzoylchloride (279 mg, 1.50 mmol) in a mixture of pyridine anddichloromethane (1:2, 9.0 mL) as per the procedure described in Step 1of Intermediate 1 to yield 362 mg of the product. ¹H NMR (300 MHz,DMSO-d₆) δ 0.68-0.75 (m, 2H), 0.93-1.01 (m, 2H), 1.93-1.97 (m, 1H), 7.08(d, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 8.18 (d, J=8.4Hz, 2H), 8.36 (d, J=8.7 Hz, 2H), 10.34 (s, 1H).

Step 2: N-(2-Chloro-4-cyclopropylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(356 mg, 1.12 mmol) with methyl iodide (85 μL, 1.34 mmol) using sodiumhydride (60% w/w, 54 mg, 1.35 mmol) in anhydrous DMF (8.0 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 364 mg of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 0.60-0.66 (m, 2H), 0.89-0.95 (m,2H), 1.83-1.87 (m, 1H), 3.25 (s, 3H), 6.98 (d, J=6.9 Hz, 1H), 7.13 (s,1H), 7.41 (d, J=8.1 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H), 8.06 (d, J=8.7 Hz,2H).

Step 3: 4-Amino-N-(2-chloro-4-cyclopropylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(352 mg, 1.06 mmol) using iron powder (178 mg, 3.19 mmol) and ammoniumchloride (570 mg, 10.64 mmol) in a mixture of ethanol and water (5:1, 12mL) as per the procedure described in Step 3 of Intermediate 1 to obtain230 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 0.65-0.71 (m, 2H),0.92-0.96 (m, 2H), 1.87-1.92 (m, 1H), 3.14 (s, 3H), 5.44 (s, 2H), 6.29(d, J=7.8 Hz, 2H), 6.94-6.99 (m, 3H), 7.17 (d, J=7.2 Hz, 2H).

Intermediate 284-Amino-N-(5-cyclopropyl-2-methylphenyl)-N-methylbenzamide

Step 1: N-(5-Cyclopropyl-2-methylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of5-cyclopropyl-2-methylaniline (558 mg, 3.79 mmol) with4-nitrobenzoylchloride (703 mg, 3.79 mmol) in a mixture of pyridine anddichloromethane (1:2, 15 mL) as per the procedure described in Step 1 ofIntermediate 1 to yield 1.1 g of the product. ¹H NMR (300 MHz, DMSO-d₆)δ 0.60-0.64 (m, 2H), 0.89-0.96 (m, 2H), 1.88-1.92 (m, 1H), 2.17 (s, 3H),6.91 (d, J=7.8 Hz, 1H), 7.05 (s, 1H), 7.15 (d, J=7.8 Hz, 1H), 8.19 (d,J=8.7 Hz, 2H), 8.36 (d, J=8.7 Hz, 2H), 10.17 (s, 1H); APCI-MS (m/z) 297(M+H)⁺.

Step 2: N-(5-Cyclopropyl-2-methylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(1.02 g, 3.44 mmol) with methyl iodide (260 μL, 4.13 mmol) using sodiumhydride (60% w/w, 165 mg, 4.13 mmol) in anhydrous DMF (10 mL) as per theprocedure described in Step 2 of Intermediate 1 to yield 1.0 g of theproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 0.39-0.42 (m, 1H), 0.60-0.65 (m,1H), 0.84-0.88 (m, 2H), 1.74-1.78 (m, 1H), 2.11 (s, 3H), 3.25 (s, 3H),6.85-6.93 (m, 2H), 7.01 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.8 Hz, 2H), 8.03(d, J=7.2 Hz, 2H).

Step 3: 4-Amino-N-(5-cyclopropyl-2-methylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(1.0 g, 3.22 mmol) using iron powder (540 mg, 9.66 mmol) and ammoniumchloride (1.7 g, 32.22 mmol) in a mixture of ethanol and water (5:1, 20mL) as per the procedure described in Step 3 of Intermediate 1 to obtain782 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 0.41-0.46 (m, 1H),0.60-0.65 (m, 1H), 0.84-0.90 (m, 2H), 1.78-1.82 (m, 1H), 2.00 (s, 3H),3.15 (s, 3H), 5.39 (s, 2H), 6.24-6.28 (m, 2H), 6.82 (d, J=7.2 Hz, 2H),6.90-6.95 (m, 2H), 6.98-6.03 (m, 1H); APCI-MS (m/z) 281 (M+H)⁺.

Intermediate 294-Amino-N-(2-chloro-5-cyclopropylphenyl)-N-methylbenzamide

Step 1: N-(2-Chloro-5-cyclopropylphenyl)-4-nitrobenzamide

The titled compound was prepared by the reaction of2-chloro-5-cyclopropylaniline (728 mg, 4.34 mmol) with4-nitrobenzoylchloride (806 mg, 4.34 mmol) in a mixture of pyridine anddichloromethane (1:2, 10 mL) as per the procedure described in Step 1 ofIntermediate 1 to yield 1.08 g of the product. ¹H NMR (300 MHz, DMSO-d₆)δ 0.65-0.69 (m, 2H), 0.95-098 (m, 2H), 1.93-1.97 (m, 1H), 7.02 (d, J=8.4Hz, 1H), 7.27 (s, 1H), 7.40 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.7 Hz, 2H),8.36 (d, J=8.7 Hz, 2H), 10.36 (s, 1H).

Step 2: N-(2-Chloro-5-cyclopropylphenyl)-N-methyl-4-nitrobenzamide

The titled compound was prepared by the reaction of Step 1 intermediate(829 mg, 2.61 mmol) with methyl iodide (196 μL, 3.14 mmol) using sodiumhydride (60% w/w, 126 mg, 3.14 mmol) in anhydrous DMF (8.0 mL) as perthe procedure described in Step 2 of Intermediate 1 to yield 841 mg ofthe product. ¹H NMR (300 MHz, DMSO-d₆) δ 0.48-0.52 (m, 1H), 0.68-0.72(m, 1H), 0.89-0.95 (m, 2H), 1.80-1.85 (m, 1H), 3.28 (s, 3H), 7.01 (d,J=9.0 Hz, 1H), 7.22-7.28 (m, 2H), 7.53 (d, J=9.0 Hz, 2H), 8.07 (d, J=8.4Hz, 2H).

Step 3: 4-Amino-N-(2-chloro-5-cyclopropylphenyl)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(830 mg, 2.50 mmol) using iron powder (419 mg, 7.51 mmol) and ammoniumchloride (1.3 g, 25.09 mmol) in a mixture of ethanol and water (5:1, 15mL) as per the procedure described in Step 3 of Intermediate 1 to obtain521 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 0.65-0.70 (m, 2H),0.88-0.95 (m, 2H), 1.83-1.87 (m, 1H), 3.16 (s, 3H), 5.43 (s, 2H),6.29-6.33 (m, 2H), 6.95-7.03 (m, 4H), 7.25-7.29 (m, 1H); APCI-MS (m/z)301 (M+H)⁺.

EXAMPLES General Procedures for the Synthesis of Examples 1□30 Method APreparation ofN-(4-chlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxyethyl)phenyl)acetamido)-N-methylbenzamide(Example 3)

Step 1: Ethyl2-(4-(2-((4-((4-chlorophenyl)(methyl)carbamoyl)phenyl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate(Example 1)

To a stirred solution of Intermediate 1 (161 mg, 0.62 mmol) andIntermediate 2 (177 mg, 0.68 mmol) in DMF (8.0 mL) were added EDCI.HCl(179 mg, 0.93 mmol), HOBt (126 mg, 0.93 mmol) and triethylamine (261 μL,1.86 mmol) at RT. The reaction was stirred overnight at RT. The reactionmixture was poured into water (20 mL) and extracted with ethyl acetate(70 mL×3). The combined organic layers were washed with brine (50 mL),dried over anhydrous sodium sulfate and concentrated. The crude materialobtained was purified by silica gel column chromatography to obtain 30mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.21 (t, J=6.9 Hz, 3H),3.33 (s, 3H), 3.70 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 7.17 (t, J=9.3 Hz,4H), 7.31 (d, J=8.7 Hz, 2H), 7.42-7.55 (m, 6H), 10.32 (s, 1H); ESI-MS(m/z) 501 (M+H)⁺.

Step 2:N-(4-Chlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxyethyl)phenyl)acetamido)-N-methylbenzamide

To a stirred solution of Step 1 intermediate (81 mg, 0.16 mmol) inmethanol (5.0 mL) at 0° C. was added sodium borohydride (13 mg, 0.33mmol). The reaction mixture was stirred at 0° C. for 1 h. The reactionwas quenched with aqueous ammonium chloride (20 mL), poured into water(20 mL) and extracted with ethyl acetate (70 mL×2). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude material obtained was purified by flashchromatography to obtain 23 mg of the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 3.34 (s, 3H), 3.67 (s, 2H), 3.78-3.84 (m, 2H), 5.58-5.62 (m,1H), 7.17 (t, J=9.3 Hz, 4H), 7.32 (d, J=8.4 Hz, 3H), 7.39-7.45 (m, 5H),10.31 (s, 1H); ESI-MS (m/z) 459 (M+H)⁺.

Method B Preparation of4-(2-(4-(2-amino-1,1-difluoro-2-oxoethyl)phenyl)acetamido)-N-(4-chlorophenyl)-N-methylbenzamide(Example 2)

To a stirred solution of ethyl2-(4-(2-((4-((4-chlorophenyl)(methyl)carbamoyl)phenyl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate(Example 1) (83 mg, 0.16 mmol) in 1,4-dioxane (5.0 mL) was added aqueousammonia (10 mL) and the reaction was stirred overnight at RT undersealed condition. The reaction was diluted with ethyl acetate (50 mL)and washed with brine (30 ml). The organic layer was concentrated underreduced pressure and triturated with diethyl ether and n-pentane toyield 26 mg of the desired product. ¹H NMR (300 MHz, DMSO-d₆) δ 3.33 (s,3H), 3.69 (s, 2H), 7.15-7.19 (m, 4H), 7.32 (d, J=8.4 Hz, 2H), 7.42-7.51(m, 6H), 7.99 (s, 1H), 8.33 (s, 1H), 10.32 (s, 1H); ESI-MS (m/z) 472(M+H)⁺.

Method C Preparation ofN-(2,5-Dichlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl) phenyl)acetamido)-N-methylbenzamide (Example 5)

Step 1: Preparation ofN-(2,5-dichlorophenyl)-4-(2-(4-(1,1-difluoro-2-oxopropyl)phenyl)acetamido)-N-methylbenzamide

To a stirred solution of Intermediate 4 (120 mg, 0.52 mmol) andIntermediate 5 (138 mg, 0.47 mmol) in DMF (5.0 mL) at 0° C. were addedN,N′-diisopropylethylamine (269 μL, 1.57 mmol) and propylphosphonicanhydride (624 μL, 1.05 mmol). The mixture was stirred overnight at RT.The reaction mixture was diluted with water (20 mL) and extracted withethyl acetate (70 mL×2). The combined organic layers were washed withbrine (100 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The crude material obtained was purified bysilica gel column chromatography to obtain 157 mg of the desiredproduct. ¹H NMR (300 MHz, CDCl₃) δ 1.93 (s, 3H), 2.32 (s, 3H), 3.70 (s,2H), 7.10-7.13 (m, 2H), 7.23-7.27 (m, 5H), 7.39 (d, J=8.1 Hz, 2H), 7.52(d, J=7.8 Hz, 2H); APCI-MS (m/z) 504 (M−H)⁻.

Step 2: N-(2,5-Dichlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 1 intermediate(137 mg, 0.27 mmol) using sodium borohydride (12 mg, 0.32 mmol) inmethanol (5.0 mL) as per the procedure described in step 2 of Method Ato yield 49 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.08 (d,J=6.3 Hz, 3H), 3.23 (s, 3H), 3.66 (s, 2H), 3.99-4.05 (m, 1H), 5.49 (d,J=6.3 Hz, 1H), 7.24 (br s, 2H), 7.36-7.44 (m, 8H), 7.71 (s, 1H), 10.30(s, 1H); APCI-MS (m/z) 506 (M−H)⁻.

Method D Preparation of4-(2-(4-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide(Example 9)

Step 1:4-(2-(4-(1,1-Difluoro-2-oxopropyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide

The titled compound was prepared by the reaction of Intermediate 8 (346mg, 1.36 mmol) with Intermediate 4 (373 mg, 1.63 mmol) in the presenceof EDCI.HCl (391 mg, 2.04 mmol), HOBt (276 mg, 2.04 mmol) andtriethylamine (570 μL, 4.08 mmol) in DMF (10 mL) as per the proceduredescribed in Step 1 of Method A to yield 194 mg of the desired product.1H NMR (300 MHz, DMSO-d₆) δ 2.12 (s, 6H), 2.33 (s, 3H), 3.27 (s, 3H),3.68 (s, 2H), 6.73 (s, 2H), 6.77 (s, 1H), 7.18 (d, J=9.0 Hz, 2H),7.40-7.52 (m, 6H), 10.27 (s, 1H).

Step 2:4-(2-(4-(1,1-Difluoro-2-hydroxy-2-methylpropyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide

To a stirred solution of Step 1 intermediate (81 mg, 0.17 mmol) in THF(15 mL) at 0° C. was added methylmagnesium bromide (50 μL, 0.43 mmol)and the mixture was stirred at 0° C. for 2 h. The mixture was quenchedwith aqueous ammonium chloride solution (20 mL) and extracted with ethylacetate (50 mL×2). The combined organic layers were washed with brine(50 mL), concentrated and the residue obtained was purified by silicagel column chromatography to obtain 32 mg of the desired product. ¹H NMR(300 MHz, DMSO-d₆) δ 1.14 (s, 6H), 2.14 (s, 6H), 3.29 (s, 3H), 3.66 (s,2H), 5.25 (s, 1H), 6.75 (s, 2H), 6.78 (s, 1H), 7.21 (d, J=7.8 Hz, 2H),7.35-7.42 (m, 6H), 10.27 (s, 1H); ESI-MS (m/z) 481 (M+H)⁺.

Method E Preparation ofN-(3,5-dichlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide (Example 21)

Step 1: Ethyl2-(4-(2-((4-((3,5-dichlorophenyl)(methyl)carbamoyl)phenyl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate

The titled compound was prepared by the reaction of Intermediate 14 (250mg, 0.84 mmol) and Intermediate 2 (219 mg, 0.84 mmol) in DMF (8.0 mL) byfollowing the procedure described in Step 1 of Method A or Step 1 ofMethod C to yield 173 mg of the product. 1H NMR (300 MHz, DMSO-d₆) δ1.22 (t, J=7.5 Hz, 3H), 3.32 (s, 3H), 3.73 (s, 2H), 4.29 (q, J=7.2 Hz,2H), 7.26 (d, J=8.1 Hz, 2H), 7.31 (s, 2H), 7.40 (s, 1H), 7.40-7.54 (m,6H), 10.35 (s, 1H).

Step 2:N-(3,5-Dichlorophenyl)-4-(2-(4-(1,1-difluoro-2-oxopropyl)phenyl)acetamido)-N-methylbenzamide

To a stirred solution of Step 1 intermediate (167 mg, 0.31 mmol) in THF(10 mL) at −78° C. was added methyl lithium (260 μL, 0.78 mmol) and themixture was gradually allowed to attain −50° C. The reaction mixture wasquenched with aqueous ammonium chloride (25 mL) and extracted with ethylacetate (70 mL×2). The combined organic layers were washed with brineand concentrated under reduced pressure. Crude was purified by flashchromatography to obtain 89 mg of the product. ¹H NMR (300 MHz, DMSO-d₆)δ 1.11 (s, 3H), 3.32 (s, 3H), 3.70 (s, 2H), 7.23 (d, J=8.7 Hz, 2H), 7.29(s, 2H), 7.31-7.37 (m, 1H), 7.42-7.52 (m, 6H), 10.32 (s, 1H).

Step 3:N-(3,5-Dichlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide

The titled compound was prepared by the reduction of Step 2 intermediate(81 mg, 0.16 mmol) using sodium borohydride (7.0 mg, 0.92 mmol) inmethanol (6.0 mL) as per the procedure described in step 2 of Method Ato yield 38 mg of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.06 (d,J=6.0 Hz, 3H), 3.32 (s, 3H), 3.68 (s, 2H), 3.99-4.04 (m, 1H), 5.49 (brs, 1H), 7.23-7.25 (d, J=8.7 Hz, 2H), 7.28-7.33 (m, 3H), 7.38-7.43 (m,4H), 7.50 (d, J=8.7 Hz, 2H), 10.32 (s, 1H); APCI-MS (m/z) 505 (M−H)⁻.

Method F Preparation of(R)—N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide (Example 29)

Step 1:N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-oxopropyl)phenyl)acetamido)-N-methylbenzamide

The titled compound was prepared by the reaction of4-amino-N-(2-chloro-4-methylphenyl)-N-methylbenzamide (Intermediate 16)(11.25 g, 40.95 mmol) and2-(4-(2-ethoxy-1,1-difluoro-2-oxoethyl)phenyl)acetic acid (Intermediate2) (12.69 g, 49.14 mmol) using N,N′-diisopropylethylamine (21 mL, 123mmol) and propylphosphonic anhydride (50% in EtOAc, 49 mL, 81.9 mmol) inDMF (150 mL) followed by reaction with methyl lithium (12.94 mL, 38.83mmol) in THF (400 mL) as per the procedure described in Step 1 and Step2 of Method E to yield 5.9 g of the product. ¹H NMR (300 MHz, DMSO-d₆) δ2.22 (s, 3H), 2.35 (s, 3H), 3.19 (s, 3H), 3.68 (s, 2H), 7.07-7.12 (m,1H), 7.23 (d, J=8.7 Hz, 2H), 7.27 (d, J=9.6 Hz, 2H), 7.31 (s, 1H), 7.39(d, J=7.5 Hz, 2H), 7.42-7.52 (m, 3H), 10.28 (s, 1H).

Step 2:(R)—N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide (Crude)

To a stirred solution of (S)-(+)-2-methyl-CBS-oxaborolidine (1M intoluene, 1.05 mL) [Ref: (i) Corey, E. J; Helal, C. J. Angew. Chem. Int.Ed. 1998, 37, 1986 □2012 (ii) Corey, E. J.; Bakshi, R. K.; Shibata, S.J. Am. Chem. Soc. 1987, 109 (18), 5551□553] in anhydrous THF (20 mL) wasadded borane dimethyl sulfide complex (214 μL, 2.25 mmol) at 0° C. andthe mixture was stirred for 30 min at the same temperature. A solutionof Step 1 Intermediate (1.0 g, 2.05 mmol) in THF (10 mL) was drop wiseadded to the reaction mixture over a period of 10 min at RT. Theresultant mixture was stirred at RT for 20 min. The reaction mixture wasquenched with methanol (10 mL) and concentrated under reduced pressure.The residue obtained was purified by flash silica gel columnchromatography to yield 721 mg of the titled product. ¹H NMR (300 MHz,DMSO-d₆) δ 1.05 (d, J=5.7 Hz, 3H), 2.22 (s, 3H), 3.20 (s, 3H), 3.65 (s,2H), 3.98-4.03 (m, 1H), 5.49 (d, J=6.0 Hz, 1H), 7.05-7.11 (m, 2H), 7.19(d, J=8.1 Hz, 2H), 7.23-7.27 (m, 2H), 7.35-7.42 (m, 5H), 10.26 (s, 1H);chiral HPLC purity: 91.40%.

Step 3:(S)—(R)-1-(4-(2-((4-((2-Chloro-4-methylphenyl)(methyl)carbamoyl)phenyl)amino)-2-oxoethyl)phenyl)-1,1-difluoropropan-2-yl2-(((benzyloxy)carbonyl)amino)-3-phenyl propanoate

To a stirred solution of Step 2 product (502 mg, 1.03 mmol),N-benzyloxycarbonyl-L-phenylalanine (487 mg, 1.54 mmol) and DIPEA (0.7mL, 4.12 mmol) in dichloromethane (20 mL) were added BOP (911 mg, 2.06mmol) and DMAP (63 mg, 0.51 mmol) at 0° C. The resultant mixture waswarmed up to RT and stirred for 16 h. The reaction mixture was dilutedwith ethyl acetate (200 mL) and washed with saturated aqueous solutionof ammonium chloride (100 mL), saturated aqueous sodium bicarbonatesolution (100 mL), water (100 mL) and brine (100 mL). The organic layerwas dried over anhydrous sodium sulfate, concentrated and the residuethus obtained was purified by flash silica gel column chromatography toyield 655 mg of the titled product. The intermediate was as such carriedforward to the next step without any characterization.

Step 4:(R)—N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide

To a stirred solution of Step 3 Intermediate (215 mg, 0.31 mmol) in amixture of THF (6.0 mL), methanol (4.0 mL) and water (2.0 mL) was addedlithium hydroxide monohydrate (39 mg, 0.93 mmol) and the mixture wasstirred at RT for 30 min. The reaction mixture was quenched with 1N HCl(10 mL) and the product was extracted in ethyl acetate (2×20 mL). Thecombined organic layers were washed with water (20 mL) and brine (10mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue obtained was purifiedby flash silica gel column chromatography to yield 93 mg of the titledproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 1.05 (d, J=5.7 Hz, 3H), 2.22 (s,3H), 3.19 (s, 3H), 3.65 (s, 2H), 3.98-4.03 (m, 1H), 5.49 (d, J=6.0 Hz,1H), 7.03-7.09 (m, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.23-7.27 (m, 2H),7.35-7.41 (m, 5H), 10.26 (s, 1H); APCI-MS (m/z) 485 (M−H)⁻; Chiral HPLCpurity: 94.76%.

Method G Preparation of(S)—N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide (Example 30)

Step 1:(S)—N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide (Crude)

To a stirred solution of (R)-(+)-2-methyl-CBS-oxaborolidine (1M intoluene, 1.05 mL) [Ref: (i) Corey, E. J; Helal, C. J. Angew. Chem. Int.Ed. 1998, 37, 1986 □012 (ii) Corey, E. J.; Bakshi, R. K.; Shibata, S. J.Am. Chem. Soc. 1987, 109 (18), 5551□553] in anhydrous THF (20 mL) wasadded borane dimethyl sulfide complex (214 μL, 2.25 mmol) at 0° C. andthe mixture was stirred for 30 min at the same temperature. A solutionofN-(2-chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-oxopropyl)phenyl)acetamido)-N-methylbenzamide(Step 1 intermediate of Example 29) (1.0 g, 2.05 mmol) in THF (10 mL)was drop wise added to the reaction mixture over a period of 10 min atRT. The resultant mixture was stirred at RT for 20 min. The reactionmixture was quenched with methanol (10 mL) and concentrated underreduced pressure. The residue obtained was purified by flash silica gelcolumn chromatography to yield 672 mg of the titled product. ¹H NMR (300MHz, DMSO-d₆) δ 1.06 (d, J=6.3 Hz, 3H), 2.22 (s, 3H), 3.20 (s, 3H), 3.65(s, 2H), 3.98-4.05 (m, 1H), 5.48 (d, J=6.0 Hz, 1H), 6.98-7.12 (m, 1H),7.20 (d, J=8.1 Hz, 2H), 7.24-7.30 (m, 2H), 7.35-7.42 (m, 6H), 10.26 (s,1H); chiral HPLC purity: 90.76%.

Step 2:(S)—(S)-1-(4-(2-((4-((2-Chloro-4-methylphenyl)(methyl)carbamoyl)phenyl)amino)-2-oxoethyl)phenyl)-1,1-difluoropropan-2-yl2-(((benzyloxy)carbonyl)amino)-3-phenylpropanoate

To a stirred solution of Step 1 product (502 mg, 1.03 mmol),N-benzyloxycarbonyl-L-phenylalanine (487 mg, 1.54 mmol) and DIPEA (0.7mL, 4.12 mmol) in dichloromethane (20 mL) were added BOP (911 mg, 2.06mmol) and DMAP (63 mg, 0.51 mmol) at 0° C. The resultant mixture waswarmed up to RT and stirred for 16 h. The reaction mixture was dilutedwith ethyl acetate (200 mL) and washed with saturated aqueous solutionof ammonium chloride (100 mL), saturated aqueous sodium bicarbonatesolution (100 mL), water (100 mL) and brine (100 mL). The organic layerwas dried over anhydrous sodium sulfate, concentrated and the residuethus obtained was purified by flash silica gel column chromatography toyield 655 mg of the titled product. The intermediate was as such carriedforward to the next step without any characterization.

Step 3:(S)—N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide

To a stirred solution of Step 2 Intermediate (270 mg, 0.39 mmol) in amixture of THF (6.0 mL), methanol (4.0 mL) and water (2.0 mL) was addedlithium hydroxide monohydrate (49 mg, 1.17 mmol) and the mixture wasstirred at RT for 30 min. The reaction mixture was quenched with 1N HCl(10 mL) and the product was extracted in ethyl acetate (2×20 mL). Thecombined organic layers were washed with water (20 mL) and brine (10mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue obtained was purifiedby flash silica gel column chromatography to yield 122 mg of the titledproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 1.06 (d, J=6.3 Hz, 3H), 2.22 (s,3H), 3.20 (s, 3H), 3.65 (s, 2H), 3.98-4.05 (m, 1H), 5.48 (d, J=6.0 Hz,1H), 6.98-7.12 (m, 1H), 7.20 (d, J=8.1 Hz, 2H), 7.24-7.29 (m, 2H),7.35-7.41 (m, 6H), 10.26 (s, 1H); APCI-MS (m/z) 485 (M−H)⁻; Chiral HPLCpurity: 92.55%.

All the examples were prepared by following the methods described abovefrom the combination of appropriate intermediates. Name, structure,Intermediate/method used and characterization data for Example 4, 6□8,10120, 10□20, 22□28 and 31□40 are given in Table 1.

TABLE 1 Chemical name, structure, Intermediate No., method ofpreparation and analytical data of Example 4, 6-8, 10-20, 22-28 and31-40 Chemical Name Example and Intermediate/ No. Structure MethodAnalytical Data Example  4

Intermediate 3 and Intermediate 5 Method C- Step 1 ¹H NMR (300 MHz,DMSO-d₆) δ 0.88 (t, J = 7.2 Hz, 3H), 2.11- 2.25 (m, 2H), 3.23 (s, 3H),3.67 (s, 2H), 7.20-7.24 (m, 2H), 7.34-7.44 (m, 8H), 7.72 (s, 1H), 10.30(br s, 1H); APCI-MS (m/z) 490 (M − H)⁻. Example  6

Intermediate 3 and Intermediate 6 Method 1 Step C ¹H NMR (300 MHz,DMSO-d₆) δ 0.87 (t, J = 7.2 Hz, 3H), 2.08- 2.25 (m, 2H), 3.21 (s, 3H),3.64 (s, 2H), 7.16-7.28 (m, 4H), 7.36-7.43 (m, 8H), 10.23 (s, 1H);ESI-MS (m/z) 457 (M + H)⁺. Example  7

Intermediate 2 and Intermediate 8 Method A ¹H NMR (300 MHz, DMSO-d₆) δ2.14 (s, 6H), 3.29 (s, 3H), 3.67 (s, 2H), 3.75-3.87 (m, 2H), 5.62 (br s,1H), 6.75 (s, 2H), 6.78 (s, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.37-7.48 (m,5H), 10.27 (s, 1H); APCI-MS (m/z) 453 (M + H)⁺. Example  8

Intermediate 4 and Intermediate 8 Method C ¹H NMR (300 MHz, DMSO-d₆) δ1.06 (d, J = 6.0 Hz, 3H), 2.14 (s, 6H), 3.29 (s, 3H), 3.66 (s, 2H),4.00-4.06 (m, 1H), 6.75 (s, 2H), 6.78 (s, 1H), 7.20 (d, J = 8.7 Hz, 2H),7.38-7.46 (m, 6H), 10.26 (s, 1H); ESI-MS (m/z) 467 (M + H)⁺. Example 10

Intermediate 7 and Intermediate 8 Method A Step 1 ¹H NMR (300 MHz,DMSO-d₆) δ 2.14 (s, 6H), 3.27-3.35 (m, 6H), 3.68 (s, 2H), 3.82-3.91 (m,2H), 6.76 (d, J = 10.5 Hz, 3H), 6.75 (s, 2H), 6.78 (s, 1H), 7.41- 7.50(m, 6H), 10.30 (s, 1H); APCI-MS (m/z) 468 (M + H)⁺. Example 11

Intermediate 3 and Intermediate 8 Method A Step 1 ¹H NMR (300 MHz,DMSO-d₆) δ 0.88 (t, J = 7.2 Hz, 3H), 2.14 (s, 6H), 2.15-2.20 (m, 2H),3.29 (s, 3H), 3.67 (s, 2H), 6.75 (s, 2H), 6.78 (s, 2H), 7.21 (d, J = 8.1Hz, 2H), 7.37-7.47 (m, 6H), 10.26 (s, 1H); APCI-MS (m/z) 451 (M + H)⁺.Example 12

Intermediate 4 and Intermediate 9 Method C ¹H NMR (300 MHz, CDCl₃) δ1.22 (d, J = 6.3 Hz, 3H), 2.29 (s, 3H), 3.48 (s, 3H), 3.69 (s, 2H),4.13-4.17 (m, 1H), 6.85 (s, 1H), 7.01 (s, 1H), 7.11-7.16 (m, 3H),7.21-7.38 (m, 7H), 7.45- 7.51 (m, 3H); APCI-MS (m/z) 548 (M + H)⁺.Example 13

Intermediate 3 and Intermediate 9 Method C Step 1 ¹H NMR (300 MHz,DMSO-d₆) δ 0.88 (t, J = 6.3 Hz, 3H), 2.18- 2.23 (m, 2H), 2.26 (s, 3H),3.36 (s, 3H), 3.67 (s, 2H), 7.05 (s, 2H), 7.15-7.28 (m, 6H), 7.39- 7.47(m, 7H), 10.27 (s, 1H); APCI-MS (m/z) 531 (M + H)⁺. Example 14

Intermediate 3 and Intermediate 10 Method C Step 1 ¹H NMR (300 MHz,DMSO-d₆) δ 0.87 (t, J = 7.8 Hz, 3H), 2.14- 2.19 (m, 2H), 3.66 (s, 2H),4.72 (q, J = 8.7 Hz, 2H), 7.05 (br s, 1H), 7.19-7.27 (m, 4H), 7.35- 7.47(m, 7H), 10.31 (s, 1H). Example 15

Intermediate 4 and Intermediate 6 Method C ¹H NMR (300 MHz, DMSO-d₆) δ1.05 (d, J = 6.3 Hz, 3H), 3.23 (s, 3H), 3.65 (s, 2H), 3.92-4.04 (m, 1H),5.48 (d, J = 6.0 Hz, 1H), 7.19-7.28 (m, 4H), 7.36- 7.42 (m, 8H), 10.26(s, 1H); APCI-MS (m/z) 473 (M + H)⁺. Example 16

Intermediate 7 and Intermediate 11 Method A Step 1 ¹H NMR (300 MHz,DMSO-d₆) δ 1.53 (d, J = 6.9 Hz, 3H), 2.61 (s, 3H), 3.31 (s, 3H), 3.72(s, 2H), 3.83-3.92 (m, 2H), 7.31- 7.54 (m, 10H), 7.66 (d, J = 8.1 Hz,2H), 10.39 (s, 1H); APCI- MS (m/z) 502 (M + H)⁺. Example 17

Intermediate 3 and Intermediate 11 Method A Step 1 ¹H NMR (300 MHz,DMSO-d₆) δ 0.89 (t, J = 7.5 Hz, 3H), 1.52 (d, J = 6.6 Hz, 3H), 2.10-2.21(m, 2H), 2.60 (s, 3H), 3.71 (s, 2H), 7.31-7.48 (m, 10H), 7.65 (d, J =8.7 Hz, 2H), 10.39 (s, 1H); APCI-MS (m/z) 485 (M + H)⁺. Example 18

Intermediate 3 and Intermediate 13 Method C Step 1 ¹H NMR (300 MHz,DMSO-d₆) δ 0.74-0.77 (m, 2H), 0.79-0.83 (m, 2H), 0.89 (t, J = 7.2 Hz,3H), 1.13 (s, 1H), 1.15-1.25 (m, 1H), 2.11-2.23 (m, 2H), 2.78 (s, 3H),3.71 (s, 2H), 7.34-7.40 (m, 2H), 7.41-7.50 (m, 8H), 7.65 (d, J = 7.5 Hz,2H), 10.38 (s, 1H). Example 19

Intermediate 4 and Intermediate 13 Method C ¹H NMR (300 MHz, DMSO-d₆) δ0.40-0.51 (m, 2H), 0.55-0.65 (m, 1H), 0.72-0.81 (m, 1H), 1.03 (d, J =6.0 Hz, 3H), 1.40- 1.45 (m, 1H), 1.87 (br s, 0.5H, rotamer), 2.15 (br s,0.5H, rotamer), 2.76 (s, 3H), 3.69 (s, 2H), 4.01 (br s, 1H), 5.49 (d, J= 6.0 Hz, 1H), 7.10-7.45 (m, 10H), 7.63 (d, J = 6.3 Hz, 2H), 10.37 (s,1H); APCI-MS (m/z) 527 (M + H)⁺. Example 20

Intermediate 3 and Intermediate 12 Method A Step 1 ¹H NMR (300 MHz,DMSO-d₆) δ 0.89 (t, J = 7.2 Hz, 3H), 1.52 (d, J = 6.3 Hz, 3H), 2.10-2.21(m, 2H), 2.61 (s, 3H), 3.72 (s, 2H), 7.30-7.45 (m, 10H), 7.66 (d, J =8.1 Hz, 2H), 10.39 (s, 1H); APCI-MS (m/z) 485 (M + H)⁺. Example 22

Intermediate 2 and Intermediate 15 Method E ¹H NMR (300 MHz, DMSO-d₆) δ2.35 (s, 3H), 3.33 (s, 3H), 3.72 (s, 2H), 7.10-7.28 (m, 5H), 7.50 (d, J= 7.8 Hz, 6H), 10.35 (s, 1H); APCI-MS (m/z) 489 (M + H)⁺. Example 23

Intermediate 2 and Intermediate 16 Method E ¹H NMR (300 MHz, DMSO-d₆) δ1.05 (d, J = 5.7 Hz, 3H), 2.22 (s, 3H), 3.20 (s, 3H), 3.65 (s, 2H),3.98-4.05 (m, 1H), 5.50 (d, J = 5.7 Hz, 1H), 7.08-7.11 (m, 1H),7.20-7.30 (m, 4H), 7.32- 7.40 (m, 6H), 10.27 (s, 1H); APCI-MS (m/z) 487(M + H)⁺. Example 24

Intermediate 2 and Intermediate 17 Method E ¹H NMR (300 MHz, DMSO-d₆) δ1.05 (d, J = 6.0 Hz, 3H), 2.08 (s, 3H), 3.18 (s, 3H), 3.63 (s, 2H),3.97-4.01 (m, 1H), 5.46 (d, J = 6.0 Hz, 1H), 7.10-7.26 (m, 5H),7.35-7.42 (m, 6H), 10.24 (s, 1H); APCI-MS (m/z) 487 (M + H)⁺. Example 25

Intermediate 2 and Intermediate 18 Method E ¹H NMR (300 MHz, DMSO-d₆) δ1.06 (d, J = 6.0 Hz, 3H), 3.21 (s, 3H), 3.66 (s, 2H), 3.99-4.06 (m, 1H),5.50 (d, J = 6.0 Hz, 1H), 7.19-7.24 (m, 2H), 7.37- 7.45 (m, 8H), 7.63(s, 1H), 10.29 (s, 1H); ESI-MS (m/z) 507 (M + H)⁺. Example 26

Intermediate 2 and Intermediate 19 Method E ¹H NMR (300 MHz, DMSO-d₆) δ1.06 (d, J = 6.0 Hz, 3H), 3.29 (s, 3H), 3.67 (s, 2H), 3.99-4.06 (m, 1H),5.50 (d, J = 6.0 Hz, 1H), 7.17-7.26 (m, 3H), 7.37- 7.48 (m, 8H), 10.31(s, 1H); ESI-MS (m/z) 491 (M + H)⁺. Example 27

Intermediate 2 and Intermediate 20 Method E ¹H NMR (300 MHz, DMSO-d₆) δ1.05 (d, J = 5.7 Hz, 3H), 2.21 (s, 3H), 3.21 (s, 3H), 3.65 (s, 2H),3.98-4.03 (m, 1H), 5.49 (d, J = 6.0 Hz, 1H), 7.04-7.10 (m, 1H),7.21-7.28 (m, 4H), 7.30- 7.44 (m, 6H), 10.27 (s, 1H); APCI-MS (m/z) 487(M + H)⁺. Example 28

Intermediate 2 and Intermediate 21 Method E ¹H NMR (300 MHz, DMSO-d₆) δ1.06 (d, J = 6.3 Hz, 3H), 2.21 (s, 3H), 3.26 (s, 3H), 3.66 (s, 2H),3.99-4.05 (m, 1H), 5.49 (d, J = 6.0 Hz, 1H), 6.96-7.05 (m, 2H), 7.22 (t,J = 8.1 Hz, 3H), 7.35-7.47 (m, 6H), 10.29 (s, 1H); APCI-MS (m/z) 472(M + H)⁺. Example 31

Intermediate 4 and Intermediate 22 Method C ¹H NMR (300 MHz, DMSO-d₆) δ1.05 (d, J = 6.3 Hz, 3H), 2.20 (s, 3H), 3.16 (s, 3H), 3.64 (s, 2H),3.98-4.04 (m, 1H), 7.16- 7.22 (m, 4H), 7.28-7.32 (m, 2H), 7.35-7.41 (m,6H), 10.27 (s, 1H); APCI-MS (m/z) 487 (M + H)⁺. Example 32

Intermediate 4 and Intermediate 23 Method C ¹H NMR (300 MHz, DMSO-d₆) δ1.05 (d, J = 6.3 Hz, 3H), 2.08 (s, 6H), 2.15 (s, 3H), 3.11 (s, 3H), 3.64(s, 2H), 4.01-4.06 (m, 1H), 5.48 (d, J = 6.0 Hz, 1H), 6.82 (s, 2H), 7.13(t, J = 8.4 Hz, 2H), 7.35-7.45 (m, 6H), 10.26 (s, 1H); APCI-MS (m/z) 481(M + H)⁺. Example 33

Intermediate 4 and Intermediate 24 Method C ¹H NMR (300 MHz, DMSO-d₆) δ1.06 (d, J = 6.3 Hz, 3H), 2.15 (s, 3H), 2.19 (s, 3H), 3.13 (s, 3H), 3.65(s, 2H), 3.98-4.04 (m, 1H), 5.49 (d, J = 6.0 Hz, 1H), 6.96-7.02 (m, 2H),7.13 (s, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.35- 7.45 (m, 5H), 10.27 (s,1H); APCI-MS (m/z) 501 (M + H)⁺. Example 34

Intermediate 4 and Intermediate 25 Method C ¹H NMR (300 MHz, DMSO-d₆) δ0.50-0.63 (m, 2H), 0.90-0.96 (m, 2H), 1.05 (d, J = 6.3 Hz, 3H),1.78-1.82 (m, 1H), 2.16 (s, 3H), 3.25 (s, 3H), 3.64 (s, 2H), 3.99-4.06(m, 1H), 5.48 (d, J = 6.0 Hz, 1H), 6.57 (s, 1H), 6.85 (d, J = 7.2 Hz,1H), 6.96 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.35-7.41 (m,6H), 10.23 (s, 1H). Example 35

Intermediate 4 and Intermediate 8 Method G ¹H NMR (300 MHz, DMSO-d₆) δ1.05 (d, J = 6.3 Hz, 3H), 2.14 (s, 6H), 3.29 (s, 3H), 3.66 (s, 2H),3.99-4.05 (m, 1H), 5.49 (br s, 1H), 6.75 (s, 2H), 6.78 (s, 1H), 7.20 (d,J = 8.7 Hz, 2H), 7.38-7.45 (m, 6H), 10.27 (s, 1H); APCI-MS (m/z) 467(M + H)⁺; chiral HPLC purity: 90.92%. Example 36

Intermediate 4 and Intermediate 8 Method F ¹H NMR (300 MHz, DMSO-d₆) δ1.06 (d, J = 6.3 Hz, 3H), 2.14 (s, 6H), 3.29 (s, 3H), 3.66 (s, 2H),3.99-4.05 (m, 1H), 5.49 (d, J = 6.0 Hz, 1H), 6.74-6.80 (m, 3H), 7.21 (d,J = 8.1 Hz, 2H), 7.38-7.45 (m, 6H), 10.27 (s, 1H); APCI-MS (m/z) 467(M + H)⁺, chiral HPLC purity: 92.88%. Example 37

Intermediate 4 and Intermediate 26 Method C ¹H NMR (300 MHz, DMSO-d₆) δ1.06 (d, J = 6.3 Hz, 3H), 2.23 (s, 3H), 3.26 (s, 3H), 3.67 (s, 2H), 4.03(br s, 1H), 5.47 (d, J = 6.0 Hz, 1H), 7.24 (d, J = 7.2 Hz, 2H),7.39-7.49 (m, 8H), 10.30 (s, 1H). Example 38

Intermediate 4 and Intermediate 27 Method C ¹H NMR (300 MHz, DMSO-d₆) δ0.61-0.65 (m, 2H), 0.82-0.92 (m, 2H), 1.04 (d, J = 6.0 Hz, 3H),1.82-1.86 (m, 1H), 3.17 (s, 3H), 3.63 (s, 2H), 3.99-4.03 (m, 1H), 5.47(d, J = 6.0 Hz, 1H), 6.94-6.98 (m, 2H), 7.10- 7.25 (m, 4H), 7.35-7.39(m, 5H), 10.24 (s, 1H). Example 39

Intermediate 4 and Intermediate 28 Method C ¹H NMR (300 MHz, DMSO-d₆) δ0.39-0.43 (m, 1H), 0.62-0.66 (m, 1H), 0.85-0.89 (m, 2H), 1.05 (d, J =5.4 Hz, 3H), 1.77- 1.83 (m, 1H), 2.03 (s, 3H), 3.20 (s, 3H), 3.64 (s,2H), 4.02-4.05 (m, 1H), 5.48 (d, J = 6.0 Hz, 1H), 6.84-6.88 (m, 2H),6.96- 7.02 (m, 2H), 7.15-7.19 (m, 2H), 7.35-7.41 (m, 5H), 10.23 (s, 1H);APCI-MS (m/z) 493 (M + H)⁺. Example 40

Intermediate 2 and Intermediate 29 Method E ¹H NMR (300 MHz, DMSO-d₆) δ0.45-0.49 (m, 1H), 0.65-0.69 (m, 1H), 0.88-0.94 (m, 2H), 1.05 (d, J =5.7 Hz, 3H), 1.82- 1.86 (m, 1H), 3.21 (s, 3H), 3.66 (s, 2H), 4.01-4.05(m, 1H), 5.48 (d, J = 6.0 Hz, 1H), 6.95-6.99 (m, 2H), 7.10-7.22 (m, 4H),7.38-7.43 (m, 5H), 10.25 (s, 1H).

Pharmacological Activity Biological Assay

The compounds described herein were screened for ROR gamma modulatoractivity using the TR-FRET assay (LanthaScreen™ available fromInvitrogen of Carlsbad, Calif.) as described in JBC 2011, 286, 26:22707-10; and Drug Metabolism and Disposition 2009, 37, 10: 2069-78.

TR-FRET Assay for ROR Gamma

The assay is based on the principle that binding of the agonist to theROR gamma causes a conformational change around helix 12 in the ligandbinding domain, resulting in higher affinity for the co-activatorpeptide. ROR gamma being constitutively active, the Fluorescein-D22co-activator peptide used in the assay is recruited in the absence of aligand. Binding of the co-activator peptide, causes an increase in theTR-FRET signal while binding of an antagonist decreases the recruitmentof the co-activator peptide, causing a decrease in the TR-FRET signalcompared to control with no compound. The assay was performed using atwo-step procedure, pre-incubation step with the compound followed bythe detection step on addition of the anti-GST tagged terbium (Tb) andfluorescein tagged fluorophores as the acceptor.

Test compounds or reference compounds such as T0901317 (Calbiochem) weredissolved in dimethylsulfoxide (DMSO) to prepare 10.0 mM stock solutionsand diluted to the desired concentration. The final concentration ofDMSO in the reaction was 4% (v/v). The assay mixture was prepared bymixing 10 nM of the GST-tagged ROR gamma ligand binding domain (LBD) inthe assay buffer containing 25 mM HEPES, 100 mM NaCl, 5 mM DTT and 0.01%BSA with or without the desired concentration of the compound. Thereaction was incubated at 22° C. for 1 hour. The pre-incubation step wasterminated by addition of the detection mixture containing 300 nMFluorescein-D22 co-activator peptide and 10 nM lantha screen Tb-anti GSTantibody into the reaction mixture. After shaking for 5 minutes thereaction was further incubated for 1 hour at room temperature and readat 4° C. on an Infinite F500 reader as per the kit instructions(Invitrogen). The inhibition of test compound was calculated based onthe TR-FRET ratio of 520/495. The activity was calculated as a percentof control reaction. IC₅₀ values were calculated from dose responsecurve by nonlinear regression analysis using GraphPad Prism software.

The compounds prepared were tested using the above assay procedure andthe results obtained are given in Table 2. Percentage inhibition atconcentrations of 1.0 μM and 10.0 μM are given in the table along withIC₅₀ (nM) details for selected examples. The compounds were found tohave IC₅₀ less than 500 nM, preferably less than 100 nM, more preferablyless than 50 nM.

The IC₅₀ (nM) values are set forth in Table 2 wherein “A” refers to anIC₅₀ value of less than 50 nM, “B” refers to IC₅₀ value in range of50.01 to 100.0 nM and “C” refers to IC₅₀ values more than 100 nM.

TABLE 2 In-vitro screening results % Inhibition at S. N. Examples No. 1μM 10 μM IC₅₀ value (nM) 1. Example 1 27.65 64.47 2. Example 2 20.7443.42 3. Example 3 74.99 85.85 C 4. Example 4 88.49 91.12 A 5. Example 587.58 94.33 A 6. Example 6 90.9 91.15 A 7. Example 7 87.52 95.06 A 8.Example 8 94.79 96.51 A 9. Example 9 86.23 96.99 C 10. Example 10 93.2295.27 A 11. Example 11 90.06 92.92 A 12. Example 12 89.4 93.68 B 13.Example 13 87.46 90.57 B 14. Example 14 84.04 87.64 A 15. Example 1585.49 92.85 A 16. Example 16 84.46 93.69 C 17. Example 17 87.13 90.77 A18. Example 18 87.37 89.98 A 19. Example 19 82.58 92.83 B 20. Example 2061.53 75.03 — 21. Example 21 82.21 87.88 A 22. Example 22 79.99 83.13 A23. Example 23 88.83 93.18 A 24. Example 24 82.62 88.71 A 25. Example 2582.03 89.97 A 26. Example 26 86.39 93.25 A 27. Example 27 90.09 91.95 A28. Example 28 90.51 93.86 A 29. Example 29 80.69 87.06 A 30. Example 3085.45 88.71 A 31. Example 31 79.13 86.63 B 32. Example 32 84.9 95.03 B33. Example 33 86.76 90.16 A 34. Example 34 91.82 92.59 A 35. Example 3589.44 93.27 A 36. Example 36 89.7 94.53 A 37. Example 37 93.94 96.3 A38. Example 38 92.6 94.77 A 39. Example 39 84.1 92.0 A 40. Example 4090.8 94.3 A (—): Not determined

1.-49. (canceled)
 50. A compound of formula (I)

or a tautomer thereof, stereoisomer thereof or pharmaceuticallyacceptable salt thereof, wherein R¹ is selected from amino, hydroxyl,C₁₋₈alkyl and C₁₋₈alkoxy; R² is selected from C₁₋₈alkyl, haloC₁₋₈alkyl,hydroxyC₁₋₈alkyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₈alkyl; R³ isselected from hydrogen, C₁₋₈alkyl, haloC₁₋₈alkyl and hydroxyC₁₋₈alkyl;R⁴ is selected from C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl,hydroxyC₁₋₈alkyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₈alkyl; eachoccurrence of R⁵ is independently selected from halogen, hydroxyl,cyano, C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl, haloC₁₋₈alkoxy,hydroxyC₁₋₈alkyl, C₃₋₆cycloalkyl and optionally substituted C₆₋₁₄aryl,wherein the substitution on C₆₋₁₄aryl is halogen; each occurrence of R⁶is independently selected from halogen, cyano, hydroxyl, C₁₋₈alkyl andC₃₋₆cycloalkyl; R^(a) and R^(b), which may be same or different, areeach independently selected from hydrogen and C₁₋₈alkyl; or R^(a) andR^(b) together may form an oxo group; ‘n’ is 1, 2, 3 or 4; ‘m’ is 0, 1or 2; and ‘p’ is 0 or
 1. 51. The compound according to claim 50, whereinR¹ is amino, hydroxyl, methyl, methoxy or ethoxy.
 52. The compoundaccording to claim 50, wherein R² is methyl or 2,2,2-trifluoroethyl. 53.The compound according to claim 50, wherein each occurrence of R⁵ isfluoro, chloro, methyl, cyclopropyl or 2-fluorophenyl.
 54. The compoundaccording to claim 50, wherein R^(a) and R^(b) are each independentlyselected from hydrogen and methyl.
 55. The compound according to claim50 selected from Ethyl2-(4-(2-((4-((4-chlorophenyl)(methyl)carbamoyl)phenyl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate,N-(4-chlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxyethyl)phenyl)acetamido)-N-methylbenzamide,4-(2-(4-(2-amino-1,1-difluoro-2-oxoethyl)phenyl)acetamido)-N-(4-chlorophenyl)-N-methylbenzamide,N-(2,5-Dichlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl) phenyl)acetamido)-N-methylbenzamide,4-(2-(4-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide,N-(3,5-dichlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,(R)—N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,(S)—N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,N-(2,5-Dichlorophenyl)-4-(2-(4-(1,1-difluoropropyl)phenyl)acetamido)-N-methylbenzamide,N-(2-Chlorophenyl)-4-(2-(4-(1,1-difluoropropyl)phenyl)acetamido)-N-methylbenzamide,4-(2-(4-(1,1-Difluoro-2-hydroxyethyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide,4-(2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide,4-(2-(4-(1,1-Difluoro-2-methoxyethyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide,4-(2-(4-(1,1-Difluoropropyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide,4-(2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)acetamido)-N-(2′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl)-N-methylbenzamide,4-(2-(4-(1,1-Difluoropropyl)phenyl)acetamido)-N-(2′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl)-N-methylbenzamide,N-(3-Chlorophenyl)-4-(2-(4-(1,1-difluoropropyl)phenyl)acetamido)-N-(2,2,2-trifluoroethyl)benzamide,N-(2-Chlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,(R)—N-(1-(4-Chlorophenyl)ethyl)-4-(2-(4-(1,1-difluoro-2-methoxyethyl)phenyl)acetamido)-N-methylbenzamide,(R)—N-(1-(4-Chlorophenyl)ethyl)-4-(2-(4-(1,1-difluoropropyl)phenyl)acetamido)-N-methylbenzamide,(R)—N-((4-chlorophenyl)(cyclopropyl)methyl)-4-(2-(4-(1,1-difluoropropyl)phenyl)acetamido)-N-methylbenzamide,N—((R)-(4-chlorophenyl)(cyclopropyl)methyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,(S)—N-(1-(4-Chlorophenyl)ethyl)-4-(2-(4-(1,1-difluoropropyl)phenyl)acetamido)-N-methylbenzamide,N-(3-Chloro-5-fluorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,N-(4-Chloro-2-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,N-(2,4-Dichlorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,N-(3-Chloro-2-fluorophenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,N-(2-Chloro-5-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,4-(2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)acetamido)-N-(2-fluoro-5-methylphenyl)-N-methylbenzamide,N-(2-Chloro-6-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,4-(2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)acetamido)-N-mesityl-N-methylbenzamide,N-(2-Chloro-4,6-dimethylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,N-(2-Cyclopropyl-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,(S)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide,(R)-4-(2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide,N-(4-Chloro-2-fluoro-5-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,N-(2-Chloro-4-cyclopropylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,N-(5-Cyclopropyl-2-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,N-(2-Chloro-5-cyclopropylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide, and pharmaceutically acceptablesalts thereof.
 56. The compound according to claim 50 selected from(R)—N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,(S)—N-(2-Chloro-4-methylphenyl)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-methylbenzamide,(R)-4-(2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide,(S)-4-(2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamido)-N-(3,5-dimethylphenyl)-N-methylbenzamide,and pharmaceutically acceptable salts thereof.
 57. A compound of theformula

or a stereoisomer thereof, or a pharmaceutically acceptable saltthereof.
 58. A pharmaceutical composition comprising a compoundaccording to claim 50 and a pharmaceutically acceptable excipient. 59.The pharmaceutical composition according to claim 58, wherein thepharmaceutically acceptable excipient is a carrier or diluent.
 60. Amethod of treating a RORγt mediated disease, disorder, syndrome, orcondition in a subject comprising administering an effective amount of acompound according to claim
 50. 61. The method according to claim 60,wherein the disease, disorder, syndrome or condition is an inflammatoryor autoimmune disease.
 62. The method according to claim 61, wherein theinflammatory or autoimmune disease is selected from rheumatoidarthritis, psoriasis, atopic dermatitis, chronic obstructive pulmonarydisease (COPD), asthma, bronchospasm, cough, multiple sclerosis,colitis, ulcerative colitis and inflammatory bowel disease.
 63. Themethod according to claim 62, wherein the disease, disorder, syndrome orcondition is chronic obstructive pulmonary disease (COPD), asthma,bronchospasm or cough.
 64. The method according to claim 62, wherein thedisease, disorder, syndrome or condition is atopic dermatitis orpsoriasis.